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Ye W, Meng X, Xu S. [Research progress on collagen secretion mechanisms in scarring]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2025; 54:266-278. [PMID: 40194913 PMCID: PMC12062945 DOI: 10.3724/zdxbyxb-2024-0535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/12/2024] [Accepted: 02/22/2025] [Indexed: 04/09/2025]
Abstract
Scar formation is characterized by dynamic alterations in collagen secretion, which critically determine scar morphology and pathological progression. In fibroblasts, collagen secretion is initiated through the activation of cytokine- and integrin-mediated signaling pathways, which promote collagen gene transcription. The procollagen polypeptide α chains undergo extensive post-translational modifications, including hydroxylation and glycosylation, within the endoplasmic reticulum (ER), followed by folding and assembly into triple-helical procollagen. Subsequent intracellular trafficking involves the sequential transport of procollagen through the ER, Golgi apparatus, and plasma membrane, accompanied by further structural refinements prior to extracellular secretion. Once secreted, procollagen is enzymatically processed to form mature collagen fibrils, which drive scar tissue remodeling. Recent advances in elucidating regulation of collagen secretion have identified pivotal molecular targets, such as transforming growth factor-beta 1 (TGF-β1), prolyl 4-hydroxylase (P4H), heat shock protein 47 (HSP47), and transport and Golgi organization protein 1 (TANGO1), providing novel therapeutic strategies to mitigate pathological scar hyperplasia and improve regenerative outcomes. This review provides a comprehensive analysis of the molecular mechanisms governing collagen secretion during scar formation, with emphasis on signaling cascades, procollagen biosynthesis, intracellular transport dynamics, and post-translational modifications, thereby offering a framework for developing targeted anti-scar therapies.
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Affiliation(s)
- Wenkai Ye
- Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xinan Meng
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, International Institutes of Medicine, Zhejiang University, Center for Membrane Receptors and Brain Medicine, International School of Medicine, Zhejiang University, Yiwu 322000, Zhejiang Province, China
| | - Suhong Xu
- Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
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Barik S, Goswami S, Nanda PK, Sarkar A, Saha B, Sarkar A, Bhattacharjee S. TGF-beta plays dual roles in immunity and pathogenesis in leishmaniasis. Cytokine 2025; 187:156865. [PMID: 39874938 DOI: 10.1016/j.cyto.2025.156865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 01/30/2025]
Abstract
Transforming growth factor-beta (TGF-β), displaying a dual role in immunosuppression and pathogenesis, has emerged as a key regulator of anti-leishmanial immune responses. In Leishmania infections, TGF-β drives immune deviation by enhancing regulatory T-cell (T-reg) differentiation and inhibiting macrophage activation, suppressing critical antiparasitic responses. This cytokine simultaneously promotes fibroblast proliferation, extracellular matrix production, and fibrosis in infected tissues, which aids in wound healing but impedes immune cell infiltration, particularly in visceral leishmaniasis, where splenic disorganization and compromised immune access are notable. In conjunction with IL-6, TGF-β modulates pathogenic Th17 responses which intensify inflammatory damage and disrupt tissue architecture. While TGF-β's immunosuppressive actions enable parasite persistence, its role in maintaining tissue integrity introduces therapeutic potential. Targeted modulation of TGF-β signaling, through selective inhibitors of TGF-β receptors or signaling intermediates, has the potential to enhance parasite clearance while minimizing immunopathology. Experimental studies suggest that phase-specific intervention strategies may allow for controlled immunostimulation or fibrosis reduction, enhancing host resistance without incurring inflammatory injury. This review discusses the intricate role of TGF-β in orchestrating immune deviation, fibrosis, and pathogenesis in leishmaniasis, proposing novel therapeutic avenues for selective modulation of TGF-β pathways to restore host immunity.
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Affiliation(s)
- Susmita Barik
- Trident Academy of Creative Technology, Bhubaneswar, Odisha, India
| | - Sanghamitra Goswami
- Department of Molecular Biology and Bioinformatics, Tripura University, Agartala, India
| | | | - Argajit Sarkar
- Department of Molecular Biology and Bioinformatics, Tripura University, Agartala, India
| | - Bhaskar Saha
- Trident Academy of Creative Technology, Bhubaneswar, Odisha, India; JSPS Government Homeopathic Medical College, Ramanthapur, Hyderabad, India
| | - Arup Sarkar
- Trident Academy of Creative Technology, Bhubaneswar, Odisha, India.
| | - Surajit Bhattacharjee
- Department of Molecular Biology and Bioinformatics, Tripura University, Agartala, India.
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Kim HW, Shin S, Park SH, Park JH, Kim SM, Lee YH, Lee MJ. Next-generation adjuvant systems containing furfurman drives potent adaptive immunity and host defense as a foot-and-mouth disease vaccine adjuvant. Front Immunol 2024; 15:1491043. [PMID: 39742276 PMCID: PMC11687127 DOI: 10.3389/fimmu.2024.1491043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/26/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction Many countries use commercial foot-and-mouth disease (FMD) vaccines to prevent FMD pandemics, but these vaccines have disadvantages, such as repeated vaccinations due to the short persistence of antibody (Ab) titers and incomplete host defense despite high Ab titers. To address these shortcomings, we aimed to develop a novel FMD vaccine containing furfurman as an adjuvant. Method To demonstrate the efficacy of the test vaccine, adaptive immunity was evaluated by measuring Ab and neutralizing Ab titers and host defense against viral infections in experimental and target animals. In addition, the expression levels of cytokines [interferon (IFN)α, IFNβ, IFNγ, interleukin (IL)-1β, IL-2, and IL-12p40] were evaluated at the early stages of vaccination to confirm the simultaneous induction of cellular and humoral immune responses induced by the test vaccine. Result The groups that received vaccine containing furfurman showed a strong early, mid-term, and long-term immune response and host defense against viral infections compared to the control groups. The significant upregulation observed in cytokine levels in the furfurman group compared to those in the control groups strongly suggest that the test vaccine strengthens cellular immune response and effectively induces a humoral immune response. Conclusion Our study demonstrated that furfurman, as an FMD vaccine adjuvant, achieves long-lasting immunity and host defense against viral infections by eliciting potent cellular and humoral immune responses. Therefore, our findings contribute to the design of next-generation FMD vaccines and highlight the potential application of furfurman as an adjuvant for other viral diseases.
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Affiliation(s)
| | | | | | | | | | | | - Min Ja Lee
- Center for Foot-and-Mouth Disease Vaccine Research, Animal and Plant Quarantine Agency, Gimcheon-si, Gyeongsangbuk-do, Republic of Korea
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Cavusoglu Nalbantoglu I, Sevgi S, Kerimoglu G, Kadıoglu Duman M, Kalyoncu NI. Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-β1/Smad2 pathway. Int J Impot Res 2024; 36:886-895. [PMID: 38454160 DOI: 10.1038/s41443-024-00868-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 02/20/2024] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Corporal tissue fibrosis is critical in diabetes-associated erectile dysfunction. Transforming growth factor-β1/Small mothers against decapentaplegic-2 (TGF-β1/Smad2) contributes to the induction of fibrosis in corporal tissue. Smad7 is accepted as a general negative regulator of Smad signaling, although its role in corporal fibrosis is unknown. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid used for biliary and liver related disorders and has antifibrotic effects in the liver. This study investigated the effects of UDCA on diabetic erectile dysfunction. Forty-eight male Spraque Dawley rats were divided into six groups: nondiabetic (n = 6), nondiabetic+20 mg/kg UDCA (n = 6), nondiabetic+80 mg/kg UDCA (n = 6), diabetic (n = 10), diabetic+20 mg/kg UDCA (n = 10), diabetic+80 mg/kg UDCA (n = 10). Diabetes was induced by intraperitoneal injection of 60 mg/kg Streptozocin. UDCA (20 and 80 mg/kg/day) or saline was subsequently administered via oral gavage for 56 days. Erectile function was evaluated as measurement of maximum intracavernosal pressure (m-ICP)/mean arterial pressure (MAP) and total ICP/MAP. Corporal tissues were evaluated by Western blotting and Masson's trichrome staining. Electrical stimulation-induced m-ICP/MAP responses were higher in UDCA-treated diabetic rats compared to untreated diabetic rats, respectively (20 mg/kg; 4 V: 0.77 ± 0.11 vs 0.45 ± 0.09, p = 0.0001 and 80 mg/kg; 4 V: 0.78 ± 0.11 vs 0.45 ± 0.09, p = 0.0001) UDCA prevented the increase in phospho-Smad2 and fibronectin protein expressions in diabetic corporal tissue both at 20 mg/kg (p = 0.0002, p = 0.002 respectively) and 80 mg/kg doses (p < 0.0001 for both). Smad7 protein expressions were significantly increased in the UDCA-treated diabetic groups compared to the untreated diabetic group (20 mg/kg: p = 0.0079; 80 mg/kg: p = 0.004). Furthermore, UDCA significantly prevented diabetes-induced increase in collagen (20 mg/kg: p = 0.0172; 80 mg/kg: p = 0.0003) and smooth muscle loss (20 mg/kg: p = 0.044; 80 mg/kg: p = 0.039). In conclusion, UDCA has a potential protective effect on erectile function in diabetic rats by altering fibrotic pathways via inhibition of TGF-β1/Smad2 and activation of Smad7.
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Affiliation(s)
- Irem Cavusoglu Nalbantoglu
- Department of Pharmacology, Graduate School of Health Sciences, Karadeniz Technical University, Trabzon, Türkiye.
| | - Serhat Sevgi
- Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
| | - Gokcen Kerimoglu
- Department of Histology and Embryology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye
| | - Mine Kadıoglu Duman
- Department of Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye
| | - Nuri Ihsan Kalyoncu
- Department of Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye
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Jia M, Liu Y, Liu J, Meng J, Cao J, Miao L, Zhang H, Zhu Y, Sun M, Yang J. Xuanfei Baidu decoction ameliorates bleomycin-elicited idiopathic pulmonary fibrosis in mice by regulating the lung-gut crosstalk via IFNγ/STAT1/STAT3 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:155997. [PMID: 39312850 DOI: 10.1016/j.phymed.2024.155997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 08/24/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia, the available treatment option is limited because the etiology and pathological process are not well understood. Although gut-lung axis reported with an emerging area of host-associated microbiota exist in many chronic lung diseases, the connection between gut-lung microbiota composition with in-site inflammation in IPF development is not yet established. PURPOSE We aimed to address the microbiota and immunity connection, and make it clear how a listed drug, Xuanfei Baidu Decoction (XFBD) affect the lung-gut crosstalk for IPF amelioration, which was previously reported for restoring disrupted lung in IPF and protecting intestinal injury. METHODS Firstly, Micro-CT (μCT) and histopathology were used to check for pathological changes in the lungs and intestines of bleomycin (BLM)-induced IPF mice. Then, Reverse Transcription and Quantitative Real-time PCR (RT-qPCR) and Western blot (WB) assays were employed to detect the integrity of the barrier of lungs and intestines in IPF mice. Subsequently, flow cytometry and 16S rRNA sequencing were used to evaluate the immune and microbial microenvironment of the lungs and intestines. We analyzed the lung-gut microbiota crosstalk for further mechanism exploration. RESULTS Firstly, we revealed that XFBD protected the integrity of the lung and intestinal barriers in the IPF mice, as evidenced by the up-regulation of ZO-1, Claudin-1, Occludin, and VE Cadherin protein expression. Then, we analyzed the changing microbiota and T cell in the gut-lung axis in IPF, and with XFBD, six highly relevant microenvironments were demonstrated that crossing damaged lung-gut barriers and XFBD could reverse these chaotic bacterial and immunity micro-environment, among them Akkermansia was an essential bacteria affecting the expression of systemic IFN-γ downstream STAT1/STAT3 axis was also studied. XFBD prominently up-regulated the production of IFN-γ and p-STAT1 and down-regulated p-STAT3, consequently exerting effects on the lung barrier and gut barrier. Taken together, XFBD ameliorated BLM-induced IPF mice by regulating IFNγ/STAT1/STAT3 axis. CONCLUSION Altogether, our results revealed that XFBD improved the BLM-elicited IPF mice by regulating gut-lung crosstalk via IFN-γ/STAT1/STAT3 axis and provided a new insight of gut-lung crosstalk in IPF, especially the dynamic changes of microorganisms in the damaged lungs needed to pay more attention during IPF therapy.
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Affiliation(s)
- Mengjie Jia
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yiman Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jia Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Junyu Meng
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jiazhen Cao
- Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High Tech Industrial Development Zone, Changchun 130117, China
| | - Lin Miao
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Han Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Yan Zhu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China
| | - Mengmeng Sun
- Changchun University of Chinese Medicine, No. 1035 Boshuo Road, Jingyue National High Tech Industrial Development Zone, Changchun 130117, China.
| | - Jian Yang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China.
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Fan W, Qu Y, Yuan X, Shi H, Liu G. Loureirin B Accelerates Diabetic Wound Healing by Promoting TGFβ/Smad-Dependent Macrophage M2 Polarization: A Concerted Analytical Approach Through Single-Cell RNA Sequencing and Experimental Verification. Phytother Res 2024. [PMID: 39532388 DOI: 10.1002/ptr.8373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Diabetic wound (DW) represent a significant clinical challenge and often fail to heal effectively. Loureirin B (LB), a flavonoid extracted from dragon's blood, has shown potential by influencing macrophage polarization and promoting wound healing. However, its mechanisms and efficacy in DW remain to be explored. This study employed single-cell RNA sequencing to analyze the classification of cells in diabetic foot ulcers and to identify the related mechanisms influenced by macrophages. Molecular docking was used to predict the interactions of LB with key proteins in the TGFβ/Smad signaling pathway. The effects of LB on macrophage polarization and wound healing were further validated through in vitro and in vivo experiments using a DW model. Single-cell analysis identified specific macrophage subtypes involved in the DW healing process and highlighted the role of the TGFβ/Smad pathway. Molecular docking suggested the potential action within the TGFβ/Smad pathway. In vitro studies showed that under high glucose conditions, LB promoted macrophage polarization from pro-inflammatory M1 to healing-promoting M2 and ECM production in fibroblasts by activating TGF-β/Smad signaling. In vivo, LB treatment enhanced wound healing rates in diabetic mice and promoted macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling. LB regulates macrophage M2 polarization and fibroblast synthesis of ECM by activating TGF-β/Smad signaling to promote DW healing. These findings suggest that LB could be a potential therapeutic agent for improving DW healing, emphasizing the need for further clinical studies to explore its efficacy and mechanisms in human subjects.
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Affiliation(s)
- Weijing Fan
- Department of Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yin Qu
- Department of Anorectal Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Yuan
- Department of Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongshuo Shi
- Department of Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guobin Liu
- Department of Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Prasad S, Singh S, Menge S, Mohapatra I, Kim S, Helland L, Singh G, Singh A. Gut redox and microbiome: charting the roadmap to T-cell regulation. Front Immunol 2024; 15:1387903. [PMID: 39234241 PMCID: PMC11371728 DOI: 10.3389/fimmu.2024.1387903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 07/31/2024] [Indexed: 09/06/2024] Open
Abstract
The gastrointestinal (GI) tract redox environment, influenced by commensal microbiota and bacterial-derived metabolites, is crucial in shaping T-cell responses. Specifically, metabolites from gut microbiota (GM) exhibit robust anti-inflammatory effects, fostering the differentiation and regulation of CD8+ tissue-resident memory (TRM) cells, mucosal-associated invariant T (MAIT) cells, and stabilizing gut-resident Treg cells. Nitric oxide (NO), a pivotal redox mediator, emerges as a central regulator of T-cell functions and gut inflammation. NO impacts the composition of the gut microbiome, driving the differentiation of pro-inflammatory Th17 cells and exacerbating intestinal inflammation, and supports Treg expansion, showcasing its dual role in immune homeostasis. This review delves into the complex interplay between GI redox balance and GM metabolites, elucidating their profound impact on T-cell regulation. Additionally, it comprehensively emphasizes the critical role of GI redox, particularly reactive oxygen species (ROS) and NO, in shaping T-cell phenotype and functions. These insights offer valuable perspectives on disease mechanisms and potential therapeutic strategies for conditions associated with oxidative stress. Understanding the complex cross-talk between GI redox, GM metabolites, and T-cell responses provides valuable insights into potential therapeutic avenues for immune-mediated diseases, underscoring the significance of maintaining GI redox balance for optimal immune health.
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Affiliation(s)
- Sujata Prasad
- Translational Division, MLM Labs, LLC, Oakdale, MN, United States
| | - Shilpi Singh
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
| | - Samuel Menge
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Iteeshree Mohapatra
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, United States
| | - Stefan Kim
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
| | - Logan Helland
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
| | - Gatikrushna Singh
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
| | - Amar Singh
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
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Li C, Ren Z, Yang G, Lei J. Mathematical Modeling of Tumor Immune Interactions: The Role of Anti-FGFR and Anti-PD-1 in the Combination Therapy. Bull Math Biol 2024; 86:116. [PMID: 39107447 DOI: 10.1007/s11538-024-01329-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/13/2024] [Indexed: 08/21/2024]
Abstract
Bladder cancer poses a significant global health burden with high incidence and recurrence rates. This study addresses the therapeutic challenges in advanced bladder cancer, focusing on the competitive mechanisms of ligand or drug binding to receptors. We developed a refined mathematical model that integrates the dynamics of tumor cells and immune responses, particularly targeting fibroblast growth factor receptor 3 (FGFR3) and immune checkpoint inhibitors (ICIs). This study contributes to understanding combination therapies by elucidating the competitive binding dynamics and quantifying the synergistic effects. The findings highlight the importance of personalized immunotherapeutic strategies, considering factors such as drug dosage, dosing schedules, and patient-specific parameters. Our model further reveals that ligand-independent activated-state receptors are the most essential drivers of tumor proliferation. Moreover, we found that PD-L1 expression rate was more important than PD-1 in driving the dynamic evolution of tumor and immune cells. The proposed mathematical model provides a comprehensive framework for unraveling the complexities of combination therapies in advanced bladder cancer. As research progresses, this multidisciplinary approach contributes valuable insights toward optimizing therapeutic strategies and advancing cancer treatment paradigms.
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Affiliation(s)
- Chenghang Li
- School of Mathematical Sciences, Tiangong University, Tianjin, 300387, China
| | - Zonghang Ren
- School of Mathematical Sciences, Tiangong University, Tianjin, 300387, China
| | - Guiyu Yang
- School of Computer Science and Technology, Tiangong University, Tianjin, 300387, China
| | - Jinzhi Lei
- School of Mathematical Sciences, Tiangong University, Tianjin, 300387, China.
- Center for Applied Mathematics, Tiangong University, Tianjin, 300387, China.
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Hou J, Feng Y, Yang Z, Ding Y, Cheng D, Shi Z, Li R, Xue L. Primary Sjögren's syndrome: new perspectives on salivary gland epithelial cells. Eur J Med Res 2024; 29:371. [PMID: 39014509 PMCID: PMC11253495 DOI: 10.1186/s40001-024-01967-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease primarily affecting exocrine glands such as the salivary glands, leading to impaired secretion and sicca symptoms. As the mainstay of salivation, salivary gland epithelial cells (SGECs) have an important role in the pathology of pSS. Emerging evidence suggests that the interplay between immunological factors and SGECs may not be the initial trigger or the sole mechanism responsible for xerostomia in pSS, challenging conventional perceptions. To deepen our understanding, current research regarding SGECs in pSS was reviewed. Among the extensive aberrations in cellular architecture and function, this review highlighted certain alterations of SGECs that were identified to occur independently of or in absence of lymphocytic infiltration. In particular, some of these alterations may serve as upstream factors of immuno-inflammatory responses. These findings underscore the significance of introspecting the pathogenesis of pSS and developing interventions targeting SGECs in the early stages of the disease.
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Affiliation(s)
- Jiaqi Hou
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Yiyi Feng
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Zhixia Yang
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Yimei Ding
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Dandan Cheng
- Shanghai Skin Diseases Hospital, 200 Wuyi Road, Changning District, Shanghai, 200050, China
| | - Zhonghao Shi
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Rouxin Li
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Luan Xue
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China.
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Oh M, Jung S, Kim YA, Lee GY, Han SN. Dietary vitamin D 3 supplementation enhances splenic NK cell activity in healthy and diabetic male mice. Nutr Res 2024; 127:144-155. [PMID: 38954977 DOI: 10.1016/j.nutres.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 07/04/2024]
Abstract
Type 2 diabetes mellitus negatively affects the immune system, resulting in reduced natural killer (NK) cell activity. Vitamin D has been shown to regulate innate and adaptive immune cells. However, the effects of vitamin D on NK cells remain inconclusive, especially in the context of diabetes. We hypothesized that dietary vitamin D3 supplementation can enhance NK cell activity in diabetic mice. Therefore, we investigated the effects of dietary vitamin D3 on NK cell activity in control and diabetic mice and explored the mechanisms of NK cell activity modulation by vitamin D3. Control (CON) and diabetic mice (db/db) were randomly divided into 2 groups, then fed either a control diet (948 IU vitamin D3/kg diet, vDC) or a diet supplemented with vitamin D3 (9,477 IU vitamin D3/kg diet, vDS) for 8 weeks. Diabetic mice exhibited lower NK cell activity than control mice. The vDS group had significantly higher NK cell activity than the vDC group in both control and diabetic mice. The vDS group had a higher percentage of CD11b single-positive NK cells than the vDC group (CON-vDS 34%; db/db-vDS 30%; CON-vDC 27%; db/db-vDC 22%). The intracellular expression of splenic TGF-β was significantly higher in the db/db group than in the CON group. Overall, vDS group had higher Bcl2 and Tbx21 mRNA expressions than the vDC group. In conclusion, the present study shows that NK cell activity is impaired under diabetic conditions, possibly due to the reduced percentage of mature NK cells. Moreover, NK activity is enhanced by dietary supplementation in both control and diabetic mice that may be associated with changes in the proportion of mature NK cells.
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Affiliation(s)
- Minha Oh
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Sohee Jung
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Yoon-Ah Kim
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Ga Young Lee
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Sung Nim Han
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea; Research Institute of Human Ecology, Seoul National University, Seoul, Republic of Korea.
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Ma Y, Shi R, Li F, Chang H. Emerging strategies for treating autoimmune disease with genetically modified dendritic cells. Cell Commun Signal 2024; 22:262. [PMID: 38715122 PMCID: PMC11075321 DOI: 10.1186/s12964-024-01641-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/28/2024] [Indexed: 05/12/2024] Open
Abstract
Gene editing of living cells has become a crucial tool in medical research, enabling scientists to address fundamental biological questions and develop novel strategies for disease treatment. This technology has particularly revolutionized adoptive transfer cell therapy products, leading to significant advancements in tumor treatment and offering promising outcomes in managing transplant rejection, autoimmune disorders, and inflammatory diseases. While recent clinical trials have demonstrated the safety of tolerogenic dendritic cell (TolDC) immunotherapy, concerns remain regarding its effectiveness. This review aims to discuss the application of gene editing techniques to enhance the tolerance function of dendritic cells (DCs), with a particular focus on preclinical strategies that are currently being investigated to optimize the tolerogenic phenotype and function of DCs. We explore potential approaches for in vitro generation of TolDCs and provide an overview of emerging strategies for modifying DCs. Additionally, we highlight the primary challenges hindering the clinical adoption of TolDC therapeutics and propose future research directions in this field.
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Affiliation(s)
- Yunhan Ma
- School of Medicine, Jiangsu University, Zhenjiang, 212000, China
| | - Ruobing Shi
- School of Medicine, Jiangsu University, Zhenjiang, 212000, China
| | - Fujun Li
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, 530000, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
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12
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Muñoz Forti K, Weisman GA, Jasmer KJ. Cell type-specific transforming growth factor-β (TGF-β) signaling in the regulation of salivary gland fibrosis and regeneration. J Oral Biol Craniofac Res 2024; 14:257-272. [PMID: 38559587 PMCID: PMC10979288 DOI: 10.1016/j.jobcr.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/13/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024] Open
Abstract
Salivary gland damage and hypofunction result from various disorders, including autoimmune Sjögren's disease (SjD) and IgG4-related disease (IgG4-RD), as well as a side effect of radiotherapy for treating head and neck cancers. There are no therapeutic strategies to prevent the loss of salivary gland function in these disorders nor facilitate functional salivary gland regeneration. However, ongoing aquaporin-1 gene therapy trials to restore saliva flow show promise. To identify and develop novel therapeutic targets, we must better understand the cell-specific signaling processes involved in salivary gland regeneration. Transforming growth factor-β (TGF-β) signaling is essential to tissue fibrosis, a major endpoint in salivary gland degeneration, which develops in the salivary glands of patients with SjD, IgG4-RD, and radiation-induced damage. Though the deposition and remodeling of extracellular matrix proteins are essential to repair salivary gland damage, pathological fibrosis results in tissue hardening and chronic salivary gland dysfunction orchestrated by multiple cell types, including fibroblasts, myofibroblasts, endothelial cells, stromal cells, and lymphocytes, macrophages, and other immune cell populations. This review is focused on the role of TGF-β signaling in the development of salivary gland fibrosis and the potential for targeting TGF-β as a novel therapeutic approach to regenerate functional salivary glands. The studies presented highlight the divergent roles of TGF-β signaling in salivary gland development and dysfunction and illuminate specific cell populations in damaged or diseased salivary glands that mediate the effects of TGF-β. Overall, these studies strongly support the premise that blocking TGF-β signaling holds promise for the regeneration of functional salivary glands.
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Affiliation(s)
- Kevin Muñoz Forti
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
| | - Gary A. Weisman
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
| | - Kimberly J. Jasmer
- Christopher S. Bond Life Sciences Center and Department of Biochemistry, University of Missouri, United States
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13
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Janho dit Hreich S, Juhel T, Leroy S, Ghinet A, Brau F, Hofman V, Hofman P, Vouret-Craviari V. Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis. eLife 2024; 12:RP88138. [PMID: 38300690 PMCID: PMC10945561 DOI: 10.7554/elife.88138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. Transcriptomic analyses show that the P2RX7/IL18/IFNG axis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an antifibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFβ. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy to help patients with lung fibrosis.
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Affiliation(s)
| | - Thierry Juhel
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
| | - Sylvie Leroy
- FHU OncoAgeNiceFrance
- Université Côte d'Azur, CNRS, Institut Pharmacologie Moléculaire et CellulaireSophia-AntipolisFrance
- Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Pneumology DepartmentNiceFrance
| | - Alina Ghinet
- Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine – Pôle recherche, Place VerdunLilleFrance
- Hautes Etudes d’Ingénieur (HEI), JUNIA Hauts-de-France, UCLille, Laboratoire de chimie durable et santéLilleFrance
- ‘Al. I. Cuza’ University of Iasi, Faculty of ChemistryIasiRomania
| | - Frederic Brau
- Université Côte d'Azur, CNRS, Institut Pharmacologie Moléculaire et CellulaireSophia-AntipolisFrance
| | - Veronique Hofman
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
- FHU OncoAgeNiceFrance
- Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur HospitalNiceFrance
- Hospital-Related Biobank (BB-0033-00025), Pasteur HospitalNiceFrance
| | - Paul Hofman
- Université Côte d’Azur, CNRS, INSERM, IRCANNiceFrance
- FHU OncoAgeNiceFrance
- Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur HospitalNiceFrance
- Hospital-Related Biobank (BB-0033-00025), Pasteur HospitalNiceFrance
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14
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Borkar NA, Thompson MA, Bartman CM, Khalfaoui L, Sine S, Sathish V, Prakash YS, Pabelick CM. Nicotinic receptors in airway disease. Am J Physiol Lung Cell Mol Physiol 2024; 326:L149-L163. [PMID: 38084408 PMCID: PMC11280694 DOI: 10.1152/ajplung.00268.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/26/2024] Open
Abstract
With continued smoking of tobacco products and expanded use of nicotine delivery devices worldwide, understanding the impact of smoking and vaping on respiratory health remains a major global unmet need. Although multiple studies have shown a strong association between smoking and asthma, there is a relative paucity of mechanistic understanding of how elements in cigarette smoke impact the airway. Recognizing that nicotine is a major component in both smoking and vaping products, it is critical to understand the mechanisms by which nicotine impacts airways and promotes lung diseases such as asthma. There is now increasing evidence that α7 nicotinic acetylcholine receptors (α7nAChRs) are critical players in nicotine effects on airways, but the mechanisms by which α7nAChR influences different airway cell types have not been widely explored. In this review, we highlight and integrate the current state of knowledge regarding nicotine and α7nAChR in the context of asthma and identify potential approaches to alleviate the impact of smoking and vaping on the lungs.
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Affiliation(s)
- Niyati A Borkar
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
| | - Michael A Thompson
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
| | - Colleen M Bartman
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
| | - Latifa Khalfaoui
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
| | - Steven Sine
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
| | - Venkatachalem Sathish
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, United States
| | - Y S Prakash
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
| | - Christina M Pabelick
- Department of Anesthesiology and Perioperative Medicine, North Dakota State University, Fargo, North Dakota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
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15
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Guo H, Yu R, Zhang H, Wang W. Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management. Int Immunopharmacol 2024; 126:111263. [PMID: 38000232 DOI: 10.1016/j.intimp.2023.111263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/11/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023]
Abstract
Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.
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Affiliation(s)
- Haochun Guo
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Ran Yu
- Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China
| | - Haijun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
| | - Wanpeng Wang
- Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China.
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16
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Mutsaers SE, Miles T, Prêle CM, Hoyne GF. Emerging role of immune cells as drivers of pulmonary fibrosis. Pharmacol Ther 2023; 252:108562. [PMID: 37952904 DOI: 10.1016/j.pharmthera.2023.108562] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/01/2023] [Accepted: 11/06/2023] [Indexed: 11/14/2023]
Abstract
The pathogenesis of pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and other forms of interstitial lung disease, involves a complex interplay of various factors including host genetics, environmental pollutants, infection, aberrant repair and dysregulated immune responses. Highly variable clinical outcomes of some ILDs, in particular IPF, have made it difficult to identify the precise mechanisms involved in disease pathogenesis and thus the development of a specific cure or treatment to halt and reverse the decline in patient health. With the advent of in-depth molecular diagnostics, it is becoming evident that the pathogenesis of IPF is unlikely to be the same for all patients and therefore will likely require different treatment approaches. Chronic inflammation is a cardinal feature of IPF and is driven by both innate and adaptive immune responses. Inflammatory cells and activated fibroblasts secrete various pro-inflammatory cytokines and chemokines that perpetuate the inflammatory response and contribute to the recruitment and activation of more immune cells and fibroblasts. The balance between pro-inflammatory and regulatory immune cell subsets, as well as the interactions between immune cell types and resident cells within the lung microenvironment, ultimately determines the extent of fibrosis and the potential for resolution. This review examines the role of the innate and adaptive immune responses in pulmonary fibrosis, with an emphasis on IPF. The role of different immune cell types is discussed as well as novel anti-inflammatory and immunotherapy approaches currently in clinical trial or in preclinical development.
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Affiliation(s)
- Steven E Mutsaers
- Institute for Respiratory Health, The University of Western Australia, Nedlands, WA, Australia.
| | - Tylah Miles
- Institute for Respiratory Health, The University of Western Australia, Nedlands, WA, Australia
| | - Cecilia M Prêle
- Institute for Respiratory Health, The University of Western Australia, Nedlands, WA, Australia; School of Medical, Molecular and Forensic Sciences, Murdoch University, WA, Australia
| | - Gerard F Hoyne
- Institute for Respiratory Health, The University of Western Australia, Nedlands, WA, Australia; The School of Health Sciences and Physiotherapy, University of Notre Dame Australia, Fremantle, WA, Australia
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17
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Wang B, Ou Z, Zhong W, Huang L, Liao W, Sheng Y, Guo Z, Chen J, Yang W, Chen K, Huang X, Yang T, Lin T, Huang J. Effective Antitumor Immunity Can Be Triggered by Targeting VISTA in Combination with a TLR3-Specific Adjuvant. Cancer Immunol Res 2023; 11:1656-1670. [PMID: 37847894 DOI: 10.1158/2326-6066.cir-23-0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 07/31/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023]
Abstract
Resistance to anti-PD-1/PD-L1 treatment is often associated with accumulation of intratumoral inhibitory macrophages. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a nonredundant immune checkpoint that can induce both T-cell and myeloid-cell immunosuppression. In this study, we found that high levels of VISTA+ immune cells were associated with advanced stage bladder cancer and predicted poor survival in patients. A combination of high infiltration of VISTA+ immune cells and PD-L1+ immune cells or PD-1+ T cells predicted the worst survival. Flow cytometry and multiplex immunofluorescence analyses confirmed that VISTA expression was higher in macrophages than in T cells or neutrophils, and only VISTA+CD163+ macrophage density predicted poor prognosis in patients with bladder cancer. Toll-like receptor (TLR) agonists are known to trigger the innate immune response in macrophages. We found that the VISTA-specific mAb 13F3 augmented the ability of a TLR3-specific adjuvant to induce macrophage activation in vitro. In the MB49 syngeneic mouse model of bladder cancer, treatment with 13F3 curbed tumor growth and prolonged survival when combined with a TLR3-specific adjuvant. The combination treatment reduced the intratumoral frequency of CD206+ anti-inflammatory macrophages and levels of the immunosuppressive molecule TGFβ1, but it upregulated expression of immunostimulatory molecules (Ifna, Ifnb, and Trail) and increased the CD8+ T cell/regulatory T-cell ratio. These findings indicate that elevated VISTA expression in immune cells, particularly macrophages, is associated with an unfavorable prognosis in patients with bladder cancer and suggest that targeting VISTA in combination with a TLR3-specific adjuvant has translational potential.
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Affiliation(s)
- Bo Wang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Ziwei Ou
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Wenlong Zhong
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Lin Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Wenjian Liao
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Yiyu Sheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Zhixing Guo
- Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, P.R. China
| | - Junyu Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Wenjuan Yang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Ke Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Xiaodong Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Tenghao Yang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
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18
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de Souza Xavier Costa N, Ribeiro Júnior G, do Nascimento ECT, de Brito JM, Antonangelo L, Faria CS, Monteiro JS, Setubal JC, Pinho JRR, Pereira RV, Seelaender M, de Castro GS, Lima JDCC, de Almeida Monteiro RA, Duarte-Neto AN, Saldiva PHN, Ferraz da Silva LF, Dolhnikoff M, Mauad T. COVID-19 induces more pronounced extracellular matrix deposition than other causes of ARDS. Respir Res 2023; 24:281. [PMID: 37964271 PMCID: PMC10648646 DOI: 10.1186/s12931-023-02555-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/05/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS. METHODS We have quantified different ECM elements and TGF-β expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile. RESULTS We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-β, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-β was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course. CONCLUSIONS Fatal COVID-19 is associated with an early TGF-β expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.
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Affiliation(s)
| | - Gabriel Ribeiro Júnior
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - Jôse Mara de Brito
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Leila Antonangelo
- Laboratório de Investigação Médica (LIM03), Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
- Divisão de Patologia Clínica, Departamento de Patologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Caroline Silvério Faria
- Laboratório de Investigação Médica (LIM03), Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | | | - João Carlos Setubal
- Departamento de Bioquímica, Instituto de Química Universidade de São Paulo, São Paulo, Brazil
| | - João Renato Rebello Pinho
- Laboratório de Investigação Médica (LIM03), Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Roberta Verciano Pereira
- Laboratório de Investigação Médica (LIM03), Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Marilia Seelaender
- Cancer Metabolism Research Group, University of São Paulo, São Paulo, Brazil
- Department of Surgery and LIM 26, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil
| | - Gabriela Salim de Castro
- Cancer Metabolism Research Group, University of São Paulo, São Paulo, Brazil
- Department of Surgery and LIM 26, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil
| | - Joanna D C C Lima
- Cancer Metabolism Research Group, University of São Paulo, São Paulo, Brazil
- Department of Surgery and LIM 26, Hospital das Clínicas, University of São Paulo, São Paulo, Brazil
| | | | - Amaro Nunes Duarte-Neto
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - Luiz Fernando Ferraz da Silva
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Serviço de Verificação de Óbitos da Capital, Universidade de São Paulo, São Paulo, Brazil
| | - Marisa Dolhnikoff
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Thais Mauad
- Departamento de Patologia (LIM 05), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- Departamento de Patologia, Laboratório de Patologia Ambiental (LIM- 05), Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, sala 1155, Cerqueira Cesar, São Paulo, Brazil.
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19
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Choi SI, Shin YC, Lee JS, Yoon YC, Kim JM, Sung MK. N-Acetylglucosamine and its dimer ameliorate inflammation in murine colitis by strengthening the gut barrier function. Food Funct 2023; 14:8533-8544. [PMID: 37655824 DOI: 10.1039/d3fo00282a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Ulcerative colitis (UC) is a chronic gastrointestinal disease whose incidence is increasing rapidly worldwide. Anti-inflammatory medications, including 5-aminosalicylic acid (5-ASA), corticosteroids, and immunosuppressants, are used for its treatment; however, new alternatives would be required due to the serious side effects of some of these medications. N-Acetylglucosamine (NAG) is an amino sugar composed of mucin that is secreted by intestinal epithelial cells. It is also used to promote the growth of intestinal bacteria. The current study aimed to determine the efficacy of NAG against dextran sulfate sodium (DSS)-induced chronic colitis and elucidate its mechanism of action. Mice were randomly divided into control, DSS, 0.1% sulfasalazine, 0.1% NAG, 0.3% NAG, and 0.3% NAG-dimer (NAG-D) groups, and results showed that colitis-induced body weight loss, disease activity, colonic tissue damage, colon length shortening, and the loss of mucin-secreting area were significantly improved in the NAG-D group. The intestinal permeability indicator, serum CD 14 level, and expression of the tight junction protein, occludin, were both improved in the 0.3% NAG group. Inflammatory biomarkers, including GATA3, IFN-γ, p-IκBα, COX2, TGF-β1, and Smad7, were significantly lower in the 0.3% NAG and NAG-D groups than in the DSS group. The intestinal microbial composition was most significantly altered in the 0.3% NAG group, showing decreased ratios of pathogenic bacteria, such as Betaproteobacteria, especially Burkholderiales. The results overall suggested that NAG or NAG-D supplementation can alleviate inflammation by strengthening the intestinal barrier function and maintaining gut microbiota homeostasis in a DSS-induced colitis mouse model.
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Affiliation(s)
- Sung-In Choi
- Department of Food and Nutrition, College of Human Ecology, Sookmyung Women's University, Chungpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea.
| | | | - Joong Su Lee
- Amicogen Inc., Jinju-si 52621, Republic of Korea
| | - Yeo Cho Yoon
- Amicogen Inc., Jinju-si 52621, Republic of Korea
| | - Ju Myung Kim
- Amicogen Inc., Jinju-si 52621, Republic of Korea
| | - Mi-Kyung Sung
- Department of Food and Nutrition, College of Human Ecology, Sookmyung Women's University, Chungpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea.
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Learmonth M, Corker A, Dasgupta S, DeLeon-Pennell KY. Regulation of cardiac fibroblasts by lymphocytes after a myocardial infarction: playing in the major league. Am J Physiol Heart Circ Physiol 2023; 325:H553-H561. [PMID: 37450290 PMCID: PMC10538980 DOI: 10.1152/ajpheart.00250.2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
Cardiac fibrosis is a pathological condition characterized by excessive accumulation of extracellular matrix components within the myocardium, which can lead to impaired cardiac function and heart failure. Studies have shown that lymphocytes including B and T cells play important roles in the development and progression of cardiac fibrosis after a myocardial infarction. In this review, we focus on the regulation of cardiac fibrosis by lymphocyte subsets, with a particular emphasis on CD4+ and CD8+ T cells and their effects on fibroblasts and cardiac remodeling. We also highlight areas for further exploration of the interactions between T cells and fibroblasts necessary for understanding and treating cardiac fibrosis and heart failure.
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Affiliation(s)
- Maya Learmonth
- College of Graduate Studies, Medical University of South Carolina, Charleston, South Carolina, United States
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Alexa Corker
- College of Graduate Studies, Medical University of South Carolina, Charleston, South Carolina, United States
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Shaoni Dasgupta
- College of Graduate Studies, Medical University of South Carolina, Charleston, South Carolina, United States
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Kristine Y DeLeon-Pennell
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
- Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States
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21
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Li X, Wu J, Zhu S, Wei Q, Wang L, Chen J. Intragraft immune cells: accomplices or antagonists of recipient-derived macrophages in allograft fibrosis? Cell Mol Life Sci 2023; 80:195. [PMID: 37395809 DOI: 10.1007/s00018-023-04846-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 07/04/2023]
Abstract
Organ fibrosis caused by chronic allograft rejection is a major concern in the field of transplantation. Macrophage-to-myofibroblast transition plays a critical role in chronic allograft fibrosis. Adaptive immune cells (such as B and CD4+ T cells) and innate immune cells (such as neutrophils and innate lymphoid cells) participate in the occurrence of recipient-derived macrophages transformed to myofibroblasts by secreting cytokines, which eventually leads to fibrosis of the transplanted organ. This review provides an update on the latest progress in understanding the plasticity of recipient-derived macrophages in chronic allograft rejection. We discuss here the immune mechanisms of allograft fibrosis and review the reaction of immune cells in allograft. The interactions between immune cells and the process of myofibroblast formulation are being considered for the potential therapeutic targets of chronic allograft fibrosis. Therefore, research on this topic seems to provide novel clues for developing strategies for preventing and treating allograft fibrosis.
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Affiliation(s)
- Xiaoping Li
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
- Department of Pediatrics, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jing Wu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Shan Zhu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Qiuyu Wei
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Liyan Wang
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Jingtao Chen
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China.
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China.
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22
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Xiong Y, Taleb M, Misawa K, Hou Z, Banerjee S, Amador-Molina A, Jones DR, Chintala NK, Adusumilli PS. c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation. NATURE CANCER 2023; 4:1001-1015. [PMID: 37336986 PMCID: PMC10765546 DOI: 10.1038/s43018-023-00573-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 05/08/2023] [Indexed: 06/21/2023]
Abstract
The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we use c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression, but no cell-surface receptor expression, of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in transforming growth factor-β-rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 co-stimulation, KITv co-stimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.
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Affiliation(s)
- Yuquan Xiong
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Meriem Taleb
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kyohei Misawa
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhaohua Hou
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Srijita Banerjee
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alfredo Amador-Molina
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David R Jones
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Navin K Chintala
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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23
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Vieri M, Rolles B, Crocioni M, Schemionek-Reinders M, Isfort S, Panse J, Brümmendorf TH, Beier F. Eltrombopag Preserves the Clonogenic Potential of Hematopoietic Stem Cells During Treatment With Antithymocyte Globulin in Patients With Aplastic Anemia. Hemasphere 2023; 7:e906. [PMID: 37304936 PMCID: PMC10249716 DOI: 10.1097/hs9.0000000000000906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 05/03/2023] [Indexed: 06/13/2023] Open
Abstract
Aplastic anemia (AA) is frequently caused by a T-cell mediated autoimmune depletion of the hematopoietic stem and progenitor cell (HSPC) compartment. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine represents the first-line treatment of AA. One side effect of ATG therapy is the release of proinflammatory cytokines such as interferon-gamma (IFN-γ), which is considered a major factor in the pathogenic autoimmune depletion of HSPC. Recently, eltrombopag (EPAG) was introduced for therapy of refractory AA patients due to its ability to bypass IFN-γ-mediated HSPC inhibition among other mechanisms. Clinical trials have evidenced that EPAG started simultaneously with IST leads to a higher response rate compared with its later administration schedules. We hypothesize that EPAG might protect HSPC from negative effects of ATG-induced release of cytokines. We observed a significant decrease in colony numbers when both healthy peripheral blood (PB) CD34+ cells and AA-derived bone marrow cells were cultured in the presence of serum from patients under ATG treatment, as compared with before treatment. Consistent with our hypothesis, this effect could be rescued by adding EPAG in vitro to both healthy and AA-derived cells. By employing an IFN-γ neutralizing antibody, we also demonstrated that the deleterious early ATG effects on the healthy PB CD34+ compartment were mediated at least partially by IFN-γ. Hence, we provide evidence for the hitherto unexplained clinical observation that concomitant use of EPAG in addition to IST comprising ATG leads to improved response in patients with AA.
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Affiliation(s)
- Margherita Vieri
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Benjamin Rolles
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Maria Crocioni
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
- Department of Medicine and Surgery, University of Perugia, Italy
| | - Mirle Schemionek-Reinders
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Susanne Isfort
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Tim H. Brümmendorf
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
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24
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Zhao Y, Qu Y, Hao C, Yao W. PD-1/PD-L1 axis in organ fibrosis. Front Immunol 2023; 14:1145682. [PMID: 37275876 PMCID: PMC10235450 DOI: 10.3389/fimmu.2023.1145682] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/09/2023] [Indexed: 06/07/2023] Open
Abstract
Fibrosis is a pathological tissue repair activity in which many myofibroblasts are activated and extracellular matrix are excessively accumulated, leading to the formation of permanent scars and finally organ failure. A variety of organs, including the lung, liver, kidney, heart, and skin, can undergo fibrosis under the stimulation of various exogenous or endogenous pathogenic factors. At present, the pathogenesis of fibrosis is still not fully elucidated, but it is known that the immune system plays a key role in the initiation and progression of fibrosis. Immune checkpoint molecules are key regulators to maintain immune tolerance and homeostasis, among which the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis has attracted much attention. The exciting achievements of tumor immunotherapy targeting PD-1/PD-L1 provide new insights into its use as a therapeutic target for other diseases. In recent years, the role of PD-1/PD-L1 axis in fibrosis has been preliminarily explored, further confirming the close relationship among PD-1/PD-L1 signaling, immune regulation, and fibrosis. This review discusses the structure, expression, function, and regulatory mechanism of PD-1 and PD-L1, and summarizes the research progress of PD-1/PD-L1 signaling in fibrotic diseases.
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Affiliation(s)
| | | | | | - Wu Yao
- *Correspondence: Wu Yao, ; Changfu Hao,
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25
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Wu X, Lin X, Tan J, Liu Z, He J, Hu F, Wang Y, Chen M, Liu F, Mao R. Cellular and Molecular Mechanisms of Intestinal Fibrosis. Gut Liver 2023; 17:360-374. [PMID: 36896620 PMCID: PMC10191785 DOI: 10.5009/gnl220045] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 05/08/2022] [Accepted: 06/03/2022] [Indexed: 03/11/2023] Open
Abstract
Intestinal fibrosis associated stricture is a common complication of inflammatory bowel disease usually requiring endoscopic or surgical intervention. Effective anti-fibrotic agents aiming to control or reverse intestinal fibrosis are still unavailable. Thus, clarifying the mechanism underpinning intestinal fibrosis is imperative. Fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins at the injured sites. Multiple cellular types are implicated in fibrosis development. Among these cells, mesenchymal cells are major compartments that are activated and then enhance the production of ECM. Additionally, immune cells contribute to the persistent activation of mesenchymal cells and perpetuation of inflammation. Molecules are messengers of crosstalk between these cellular compartments. Although inflammation is necessary for fibrosis development, purely controlling intestinal inflammation cannot halt the development of fibrosis, suggesting that chronic inflammation is not the unique contributor to fibrogenesis. Several inflammation-independent mechanisms including gut microbiota, creeping fat, ECM interaction, and metabolic reprogramming are involved in the pathogenesis of fibrosis. In the past decades, substantial progress has been made in elucidating the cellular and molecular mechanisms of intestinal fibrosis. Here, we summarized new discoveries and advances of cellular components and major molecular mediators that are associated with intestinal fibrosis, aiming to provide a basis for exploring effective anti-fibrotic therapies in this field.
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Affiliation(s)
- Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoxuan Lin
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zishan Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinshen He
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fan Hu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yu Wang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fen Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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26
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Xu H, Zhao F, Wu D, Zhang Y, Bao X, Shi F, Cai Y, Dou J. Eliciting effective tumor immunity against ovarian cancer by cancer stem cell vaccination. Biomed Pharmacother 2023; 161:114547. [PMID: 36933377 DOI: 10.1016/j.biopha.2023.114547] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
Advanced ovarian cancer (OC) patients have limited benefit from current relevant cytotoxic and targeted therapies following debulking surgery. Therefore, new therapeutic strategies are in urgent need. Immunotherapy has shown great potential in tumor treatment, especially in tumor vaccine development. The study objective was to evaluate the immune effects of cancer stem cells (CSCs) vaccines on OC. The CD44+CD117+CSCs were isolated from human OC HO8910 and SKOV3 cells using the magnetic cell sorting system; the cancer stem-like cells were selected from murine OC ID8 cell by no-serum formed sphere culture. The CSC vaccines were prepared by freezing and thawing these CSCs, which were then injected into mice followed by challenging the different OC cells. The in vivo antitumor efficacy of CSC immunization revealed the vaccines were capable of significantly provoking immune responses to autologous tumor antigens in vaccinated mice as the mice were found to have markedly inhibited tumor growth, prolonged survival, and decreased CSC counts in OC tissues when compared to mice without the CSC vaccination. The in vitro cytotoxicities of immunocytes toward SKOV3, HO8910 and ID8 cells indicated a significant killing efficacy compared with the controls. However, the antitumor efficacy was remarkably reduced whilst the mucin-1 expression in CSC vaccines was down-regulated by small interfering RNA. Overall, findings from this study provided the evidence that has deepened our understanding of CSC vaccine immunogenicity and anti-OC efficacy, particularly for the role of dominant antigen mucin-1. It is possible to turn the CSC vaccine into an immunotherapeutic approach against ovarian cancer.
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Affiliation(s)
- Hui Xu
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China; Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Fengshu Zhao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China
| | - Di Wu
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yunxia Zhang
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xueyang Bao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China
| | - Fangfang Shi
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yunlang Cai
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jun Dou
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing 210009, China.
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27
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Matthiesen S, Christiansen B, Jahnke R, Zaeck LM, Karger A, Finke S, Franzke K, Knittler MR. TGF-β/IFN-γ Antagonism in Subversion and Self-Defense of Phase II Coxiella burnetii -Infected Dendritic Cells. Infect Immun 2023; 91:e0032322. [PMID: 36688662 PMCID: PMC9933720 DOI: 10.1128/iai.00323-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 12/20/2022] [Indexed: 01/24/2023] Open
Abstract
Dendritic cells (DCs) belong to the first line of innate defense and come into early contact with invading pathogens, including the zoonotic bacterium Coxiella burnetii, the causative agent of Q fever. However, the pathogen-host cell interactions in C. burnetii-infected DCs, particularly the role of mechanisms of immune subversion beyond virulent phase I lipopolysaccharide (LPS), as well as the contribution of cellular self-defense strategies, are not understood. Using phase II Coxiella-infected DCs, we show that impairment of DC maturation and MHC I downregulation is caused by autocrine release and action of immunosuppressive transforming growth factor-β (TGF-β). Our study demonstrates that IFN-γ reverses TGF-β impairment of maturation/MHC I presentation in infected DCs and activates bacterial elimination, predominantly by inducing iNOS/NO. Induced NO synthesis strongly affects bacterial growth and infectivity. Moreover, our studies hint that Coxiella-infected DCs might be able to protect themselves from mitotoxic NO by switching from oxidative phosphorylation to glycolysis, thus ensuring survival in self-defense against C. burnetii. Our results provide new insights into DC subversion by Coxiella and the IFN-γ-mediated targeting of C. burnetii during early steps in the innate immune response.
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Affiliation(s)
- Svea Matthiesen
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Bahne Christiansen
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Rico Jahnke
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Luca M. Zaeck
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Axel Karger
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Kati Franzke
- Institute of Infectology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Michael R. Knittler
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
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28
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Wang F, Wang S, Zhang C, Tian X, Zhou Y, Xuan W, Matteson EL, Luo F, Tschumperlin D, Vassallo R. Noncanonical JAK1/STAT3 interactions with TGF-β modulate myofibroblast transdifferentiation and fibrosis. Am J Physiol Lung Cell Mol Physiol 2022; 323:L698-L714. [PMID: 36283961 DOI: 10.1152/ajplung.00428.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited survival. Janus kinases (JAKs), tyrosine kinases that transduce cytokine-mediated signals, are known to be involved, but their specific roles in lung fibrosis are not well defined. In this study, the interactions between JAK1/signal transducers and activators of transcription (STAT)3 signaling and transforming growth factor-beta (TGF-β)-induced fibroblast responses were investigated using both pharmacological and siRNA approaches in human normal and IPF-derived lung fibroblasts. We found that JAK1 directly interacts with the TGF-β receptor I subunit (TβRI), and silencing JAK1 promotes myofibroblast transdifferentiation. However, the suppression of JAK1 signaling in vitro and in vivo using an inhibitor (upadacitinib) did not alter lung fibroblast activation or fibrosis development. STAT3 was constitutively active in cultured primary lung fibroblasts; this STAT3 activation required JAK1 and repressed myofibroblast transdifferentiation. Loss of phosphorylated STAT3 following transcriptional JAK1 silencing promoted myofibroblast transdifferentiation. In contrast, transcriptional silencing of unphosphorylated STAT3 suppressed TGF-β signaling, decreased SMAD3 activation, and reduced myofibroblast transdifferentiation and ECM production. Taken together, these observations support a role for JAK1/STAT3 as a direct regulator of TGF-β signaling in lung fibroblasts. Modulation of JAK1/STAT3 signaling in lung fibroblasts represents a noncanonical approach to regulating TGF-β-induced fibrosis and suggests the potential for a novel approach to treat pulmonary fibrosis.
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Affiliation(s)
- Faping Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Shaohua Wang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Chujie Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Xue Tian
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Yongfang Zhou
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Weixia Xuan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Eric L Matteson
- Division of Rheumatology and Department of Health Science Research, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Daniel Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Robert Vassallo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.,Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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29
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Gauthier T, Chen W. IFN-γ and TGF-β, Crucial Players in Immune Responses: A Tribute to Howard Young. J Interferon Cytokine Res 2022; 42:643-654. [PMID: 36516375 PMCID: PMC9917322 DOI: 10.1089/jir.2022.0132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/18/2022] [Indexed: 12/15/2022] Open
Abstract
Interferon gamma (IFN-γ) and transforming growth factor beta (TGF-β), both pleiotropic cytokines, have been long studied and described as critical mediators of the immune response, notably in T cells. One of the investigators who made seminal and critical discoveries in the field of IFN-γ biology is Dr. Howard Young. In this review, we provide an overview of the biology of IFN-γ as well as its role in cancer and autoimmunity with an emphasis on Dr. Young's critical work in the field. We also describe how Dr. Young's work influenced our own research studying the role of TGF-β in the modulation of immune responses.
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Affiliation(s)
- Thierry Gauthier
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland, USA
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland, USA
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30
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Jiang X, Peng Y, Liu L, Wang Y, Li M, Li W, Huang F, Zheng C, Xu F, Hu Q, Wei W, Dong S, Zhao Q. MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver Int 2022; 42:2743-2758. [PMID: 36181707 DOI: 10.1111/liv.15445] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/08/2022] [Accepted: 09/29/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that display a critical role in various liver diseases. However, the role of MAIT cells in cholestatic liver fibrogenesis remains obscure. Our study aims to assess the contribution of MAIT cells and underlying mechanisms during this process. METHODS Cholestatic murine models using MAIT cell-deficient (MR1- /- ) and wild-type (WT) mice were established by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet or bile duct ligation (BDL). Liver samples were collected to determine the severity of fibrosis. Lymphocytes of the liver were isolated for analysing the phenotype and function of MAIT cells. Cell co-culture experiments were performed to investigate the cross-talk between MAIT and NK cells. RESULTS Liver MAIT cells were more activated with increased cytokines in cholestatic mice models than in control mice, although their frequency was decreased. MAIT cell deficiency led to severe liver inflammation and fibrosis with more activated HSCs in cholestatic mice. In addition, MR1- /- mice had an increased frequency of NK cells with higher expression of stimulatory receptors relative to WT mice. Paradoxically, activated MAIT cells significantly promoted the anti-fibrotic ability of NK cells by enhancing their cytotoxicity against HSCs in co-culture experiments. Importantly, this effect depended on direct cell-cell contact and TNF-α produced by MAIT cells. CONCLUSION Our findings indicate that MAIT cells ameliorate cholestatic liver fibrosis by enhancing the cytotoxicity of NK cells against HSCs. An in-depth understanding of the MAIT cell-mediated regulatory effect will provide more valuable immunotherapy strategies to treat liver fibrosis.
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Affiliation(s)
- Xiang Jiang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Youwei Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Mengting Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Wenjie Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fengxing Huang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Chunlan Zheng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Fei Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qian Hu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Wanhui Wei
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Shouquan Dong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
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Schuler C, Foti F, Perren L, Mamie C, Weder B, Stokmaier M, de Vallière C, Heuchel R, Ruiz PA, Rogler G, Hausmann M. Deletion of Smad7 Ameliorates Intestinal Inflammation and Contributes to Fibrosis. Inflamm Bowel Dis 2022; 29:647-660. [PMID: 36282601 DOI: 10.1093/ibd/izac221] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of transforming growth factor (TGF)-β compared with non-IBD controls. SMAD7 negatively regulates TGF-β signaling. An earlier study aiming to target Smad7 showed a lack of clinical benefit. It remains unknown whether inhibition of SMAD7 is beneficial in specific settings of IBD. We evaluated the effect of Smad7 deficiency on inflammation, fibrogenesis, and wound healing. METHODS For the initiation of fibrosis in Smad7-/- (Smad7Δex-I) CD-1 mice, the dextran sodium sulfate-induced chronic colitis model and the heterotopic transplantation model of fibrosis were used. Wound closure of fibroblasts from Smad7-/- mice was determined using culture inserts and electric cell-substrate impedance sensing in vitro. RESULTS In dextran sodium sulfate-induced chronic colitis, Smad7 deficiency was associated with ameliorated inflammation, as evidenced by decreased clinical score, histological score, and myeloperoxidase activity. Absence of SMAD7 decreased T-cell accumulation in colonic tissue and tumor necrosis factor (TNF) mRNA expression levels. Smad7-/- mice showed a significant increase in hydroxyproline and collagen content, as well as ColIVa1 mRNA expression. Wild type mice transplanted with terminal ileum from Smad7-/- mice in the heterotopic animal model for intestinal fibrosis showed a significant increase in collagen content and protein expression of α-smooth muscle actin. CONCLUSIONS Smad7 deficiency is associated with a decrease in intestinal inflammation and an increase in fibrosis. Targeting SMAD7 constitutes a potential new treatment option for IBD; progression of disease-associated fibrosis should be considered.
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Affiliation(s)
- Cordelia Schuler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Federica Foti
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Leonie Perren
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Michelle Stokmaier
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Rainer Heuchel
- Pancreas Cancer Research Lab, CLINTEC, Karolinska Institutet, Huddinge, Sweden
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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32
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Ikeda M, Ide T, Matsushima S, Ikeda S, Okabe K, Ishikita A, Tadokoro T, Sada M, Abe K, Sato M, Hanada A, Arai S, Ohtani K, Nonami A, Mizuno S, Morimoto S, Motohashi S, Akashi K, Taniguchi M, Tsutsui H. Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model. Circ Heart Fail 2022; 15:e009366. [PMID: 36268712 PMCID: PMC9760469 DOI: 10.1161/circheartfailure.122.009366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated. METHODS Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin TΔK210/ΔK210 with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. RESULTS The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 (Angpt1) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated Angpt1 expression in cardiomyocytes via Stat1. CONCLUSIONS Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.
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Affiliation(s)
- Masataka Ikeda
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Immunoregulatory Cardiovascular Medicine (M.I., T.I.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomomi Ide
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Immunoregulatory Cardiovascular Medicine (M.I., T.I.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shouji Matsushima
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Soichiro Ikeda
- Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kosuke Okabe
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihito Ishikita
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonori Tadokoro
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masashi Sada
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ko Abe
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Midori Sato
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiko Hanada
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinobu Arai
- Department of Early Childhood and Elementary Education, Faculty of Education, Nakamura Gakuen University, Fukuoka, Japan (S.A.)
| | - Kisho Ohtani
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Nonami
- Center for Advanced Medical Innovation, Kyushu University Hospital, Fukuoka, Japan (A.N.)
| | - Shinichi Mizuno
- Department of Health Sciences (S. Mizuno), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sachio Morimoto
- Department of Health Sciences at Fukuoka, International University of Health and Welfare, Japan (S. Morimoto)
| | - Shinichiro Motohashi
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Medical Immunology, Graduate School of Medicine, Chiba University, Japan (S. Motohashi)
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science (K. Akashi), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Taniguchi
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (M.T.)
| | - Hiroyuki Tsutsui
- Department of Cardiovascular Medicine (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Cardiovascular Medicine, Research Institute of Angiocardiology (M.I., T.I., S.M., S.I., K.O., A.I., T.T., M.S., K. Abe, M.S., A.H., K.O., H.T.), Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
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33
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Tan Z, Wang L, Li X. Composition and regulation of the immune microenvironment of salivary gland in Sjögren’s syndrome. Front Immunol 2022; 13:967304. [PMID: 36177010 PMCID: PMC9513852 DOI: 10.3389/fimmu.2022.967304] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by exocrine gland dysfunction and inflammation. Patients often have dry mouth and dry eye symptoms, which seriously affect their lives. Improving dry mouth and eye symptoms has become a common demand from patients. For this reason, researchers have conducted many studies on external secretory glands. In this paper, we summarize recent studies on the salivary glands of pSS patients from the perspective of the immune microenvironment. These studies showed that hypoxia, senescence, and chronic inflammation are the essential characteristics of the salivary gland immune microenvironment. In the SG of pSS, genes related to lymphocyte chemotaxis, antigen presentation, and lymphocyte activation are upregulated. Interferon (IFN)-related genes, DNA methylation, sRNA downregulation, and mitochondrial-related differentially expressed genes are also involved in forming the immune microenvironment of pSS, while multiple signaling pathways are involved in regulation. We further elucidated the regulation of the salivary gland immune microenvironment in pSS and relevant, targeted treatments.
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34
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Choi SH, Huang AY, Letterio JJ, Kim BG. Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase. Front Immunol 2022; 13:932412. [PMID: 36045676 PMCID: PMC9420841 DOI: 10.3389/fimmu.2022.932412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.
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Affiliation(s)
- Sung Hee Choi
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Alex Y. Huang
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- The Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals (UH) Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
| | - John J. Letterio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- The Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals (UH) Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
| | - Byung-Gyu Kim
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- *Correspondence: Byung-Gyu Kim,
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35
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Singh S, Allwood BW, Chiyaka TL, Kleyhans L, Naidoo CC, Moodley S, Theron G, Segal LN. Immunologic and imaging signatures in post tuberculosis lung disease. Tuberculosis (Edinb) 2022; 136:102244. [PMID: 36007338 PMCID: PMC10061373 DOI: 10.1016/j.tube.2022.102244] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/24/2022] [Accepted: 07/31/2022] [Indexed: 11/25/2022]
Abstract
Post Tuberculosis Lung Disease (PTLD) affects millions of tuberculosis survivors and is a global health burden. The immune mechanisms that drive PTLD are complex and have historically been under investigated. Here, we discuss two immune-mediated paradigms that could drive human PTLD. We review the characteristics of a fibrotic granuloma that favors the development of PTLD via an abundance of T-helper-2 and T-regulatory cells and an upregulation of TGF-β mediated collagen deposition. Next, we discuss the post-primary tuberculosis paradigm and the complex mixture of caseous pneumonia, cavity formation and fibrosis that can also lead to PTLD. We review the delicate balance between cellular subsets and cytokines of the innate and adaptive immune system in conjunction with host-derived proteases that can perpetuate the parenchymal lung damage seen in PTLD. Next, we discuss the role of novel host directed therapies (HDT) to limit the development of PTLD and in particular, the recent repurposing of established medications such as statins, metformin and doxycycline. Finally, we review the emerging role of novel imaging techniques as a non-invasive modality for the early recognition of PTLD. While access to computed tomography imaging is unlikely to be available widely in countries with a high TB burden, its use in research settings can help phenotype PTLD. Due to a lack of disease-specific biomarkers and controlled clinical trials, there are currently no evidence-based recommendations for the management of PTLD. It is likely that an integrated antifibrotic strategy that could simultaneously target inflammatory and pro-fibrotic pathways will probably emerge as a successful way to treat this complex condition. In a disease spectrum as wide as PTLD, a single immunologic or radiographic marker may not be sufficient and a combination is more likely to be a successful surrogate that could aid in the development of successful HDTs.
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Affiliation(s)
- S Singh
- NYU Langone Translational Lung Biology Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, NYU Langone Health, 550 First Avenue, MSB 594, New York, NY, USA.
| | - B W Allwood
- Division of Pulmonology, Department of Medicine, Stellenbosch University & Tygerberg Hospital, South Africa.
| | - T L Chiyaka
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
| | - L Kleyhans
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
| | - C C Naidoo
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
| | - S Moodley
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
| | - G Theron
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa.
| | - L N Segal
- NYU Langone Translational Lung Biology Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, NYU Langone Health, 550 First Avenue, MSB 594, New York, NY, USA.
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36
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Pacheco-Hernández LM, Ramírez-Noyola JA, Gómez-García IA, Ignacio-Cortés S, Zúñiga J, Choreño-Parra JA. Comparing the Cytokine Storms of COVID-19 and Pandemic Influenza. J Interferon Cytokine Res 2022; 42:369-392. [PMID: 35674675 PMCID: PMC9422807 DOI: 10.1089/jir.2022.0029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/19/2022] [Indexed: 12/15/2022] Open
Abstract
Emerging respiratory viruses are major health threats due to their potential to cause massive outbreaks. Over the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has caused millions of cases of severe infection and deaths worldwide. Although natural and vaccine-induced protective immune mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been increasingly identified, the factors that determine morbimortality are less clear. Comparing the immune signatures of COVID-19 and other severe respiratory infections such as the pandemic influenza might help dissipate current controversies about the origin of their severe manifestations. As such, identifying homologies in the immunopathology of both diseases could provide targets for immunotherapy directed to block shared pathogenic mechanisms. Meanwhile, finding unique characteristics that differentiate each infection could shed light on specific immune alterations exploitable for diagnostic and individualized therapeutics for each case. In this study, we summarize immunopathological aspects of COVID-19 and pandemic influenza from the perspective of cytokine storms as the driving force underlying morbidity. Thereby, we analyze similarities and differences in the cytokine profiles of both infections, aiming to bring forward those molecules more attractive for translational medicine and drug development.
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Affiliation(s)
- Lynette Miroslava Pacheco-Hernández
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Jazmín Ariadna Ramírez-Noyola
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Programa de Maestría en Ciencias de la Salud, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón and Plan de San Luis, Mexico City, Mexico
| | - Itzel Alejandra Gómez-García
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Sergio Ignacio-Cortés
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Joaquín Zúñiga
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - José Alberto Choreño-Parra
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas,” Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
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Yang L, Sun L, Cao Y, Wang Q, Song A, Zhu R, Liu W, Lu S. MULT1-Encoding DNA Alleviates Schistosomiasis-Associated Hepatic Fibrosis via Modulating Cellular Immune Response. J Inflamm Res 2022; 15:4027-4045. [PMID: 35873385 PMCID: PMC9301018 DOI: 10.2147/jir.s354224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 07/07/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose In schistosomiasis-associated hepatic fibrosis, the role of murine UL16-binding protein-like transcript 1 (MULT1), the strongest ligand of natural killer group 2-member D receptor (NKG2D), remains unclear. Here, Schistosoma japonicum-infected mice administered with MULT1-encoding DNA were used to test MULT1 as a potential therapy for schistosomiasis-associated hepatic fibrosis and explore relevant mechanisms. Materials and Methods A recombinant plasmid encoding MULT1 (p-rMULT1) was constructed and administered to Schistosoma japonicum-infected BALB/c mice via hydrodynamic tail vein injection. Egg granulomas in liver, hepatic fibrosis biomarkers and levels of cytokines were investigated. Comparisons of CD4+ T, CD8+ T, NK and NKT proportions as well as their phenotype were performed not only between Schistosoma infected, p-rMULT1 treated group and Schistosoma infected, backbone plasmid pEGFP-N1 treated group but also between infected, nontreated group and health control group. Results Reduced area of granuloma formation and fibrosis around single eggs, downregulated expression of collagen I, α-smooth muscle actin, TGF-β and IL-10, and upregulated expression of IFN-γ, were observed in the livers of p-rMULT1 treated mice. p-rMULT1 treatment improved Schistosoma infection impacted immune microenvironment by modulating proportion of CD4+ T CD8+ T, natural killer (NK) and NKT cells, enhancing expression of NKG2D, in lymphocytes, and augmenting IFN-γ secretion by CD4+ T, CD8+ T, NK and NKT cells, as well as partially reversing some other phenotype changes of lymphocytes. Conclusion To the best of our knowledge, we provided the first in vivo evidence that MULT1 is a favorable anti-fibrosis factor in the context of schistosomiasis. The inhibitory effect of MULT1 overexpression on schistosomiasis associated with hepatic fibrosis may result from augmenting the proportion and function of NKG2D-expressing immune cells, and from enhancing NK- and T-cell activation, as well as regulating the helper T (Th)1/Th2 balance.
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Affiliation(s)
- Lu Yang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Li Sun
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yalan Cao
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Wang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.,Department of Histology and Embryology, School of Basic Medicine, Guizhou Medical University, Guiyang, People's Republic of China
| | - Anni Song
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Ru Zhu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Wenqi Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shengjun Lu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Akoolo L, Djokic V, Rocha SC, Ulloa L, Parveen N. Sciatic-Vagal Nerve Stimulation by Electroacupuncture Alleviates Inflammatory Arthritis in Lyme Disease-Susceptible C3H Mice. Front Immunol 2022; 13:930287. [PMID: 35924250 PMCID: PMC9342905 DOI: 10.3389/fimmu.2022.930287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 11/25/2022] Open
Abstract
Lyme disease is caused by Borrelia burgdorferi, and the pathogenesis of the disease is complex with both bacterial and host factors contributing to inflammatory responses. Lyme disease affects different organs including joints and results in arthritis. Immune responses stimulated by B. burgdorferi through toll-like receptors cause infiltration of leukocytes, which produce inflammatory cytokines and facilitate spirochete clearance. However, arthritic manifestations and chronic fatigue syndrome-like symptoms persist long after completion of antibiotic treatment regimens in a significant number of patients. To counter the effects of inflammation, treatment by non-steroidal anti-inflammatory drugs, hydroxychloroquine, or synovectomy to eradicate inflammatory arthritis in the involved joint could be employed; however, they often have long-term consequences. Acupuncture has been used for a long time in Asian medicine to diminish pain during various ailments, but the effects and its mechanism are just beginning to be explored. Control of inflammation by neuronal stimulation has been exploited as a systemic therapeutic intervention to arrest inflammatory processes. Our objective was to determine whether activation of the sciatic-vagal network by electroacupuncture on ST36 acupoint, which is used to control systemic inflammation in experimental models of infectious disorders such as endotoxemia, can also alleviate Lyme arthritis symptoms in mice. This aim was further strengthened by the reports that sciatic-vagal neuronal network stimulation can lead to dopamine production in the adrenal medulla and moderate the production of inflammatory factors. We first assessed whether electroacupuncture affects spirochete colonization to attenuate Lyme arthritis. Interestingly, bioluminescent B. burgdorferi burden detected by live imaging and qPCR were similar in electroacupuncture- and mock-treated mice, while electroacupuncture induced a lasting anti-inflammatory effect on mice. Despite the discontinuation of treatment at 2 weeks, the simultaneous decrease in neutrophils in the joints and inflammatory cytokine levels throughout the body at 4 weeks suggests a systemic and persistent effect of electroacupuncture that attenuates Lyme arthritis. Our results suggest that electroacupuncture-mediated anti-inflammatory responses could offer promising healthcare benefits in patients suffering from long-term Lyme disease manifestations.
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Affiliation(s)
- Lavoisier Akoolo
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Vitomir Djokic
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Sandra C. Rocha
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Luis Ulloa
- Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University, Durham, NC, United States
| | - Nikhat Parveen
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States
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BMP Signaling Pathway in Dentin Development and Diseases. Cells 2022; 11:cells11142216. [PMID: 35883659 PMCID: PMC9317121 DOI: 10.3390/cells11142216] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/08/2022] [Accepted: 07/12/2022] [Indexed: 12/27/2022] Open
Abstract
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.
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40
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Yang H, Sinha N, Rand U, Hauser H, Köster M, de Greef TFA, Tel J. A universal microfluidic approach for integrated analysis of temporal homocellular and heterocellular signaling and migration dynamics. Biosens Bioelectron 2022; 211:114353. [PMID: 35594624 DOI: 10.1016/j.bios.2022.114353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/26/2022] [Accepted: 05/06/2022] [Indexed: 11/24/2022]
Abstract
Microfluidics offers precise and dynamic control of microenvironments for the study of temporal cellular responses. However, recent research focusing solely on either homocellular (single-cell, population) or heterocellular response may yield insufficient output, which possibly leads to partial comprehension about the underlying mechanisms of signaling events and corresponding cellular behaviors. Here, a universal microfluidic approach is developed for integrated analysis of temporal signaling and cell migration dynamics in multiple cellular contexts (single-cell, population and coculture). This approach allows to confine the desired number or mixture of specific cell sample types in a single device. Precise single cell seeding was achieved manually with bidirectional controllability. Coupled with time-lapse imaging, temporal cellular responses can be observed with single-cell resolution. Using NIH3T3 cells stably expressing signal transducer and activator of transcription 1/2 (STAT1/2) activity biosensors, temporal STAT1/2 activation and cell migration dynamics were explored in isolated single cells, populations and cocultures stimulated with temporal inputs, such as single-pulse and continuous signals of interferon γ (IFNγ) or lipopolysaccharide (LPS). We demonstrate distinct dynamic responses of fibroblasts in different cellular contexts. Our presented approach facilitates a multi-dimensional understanding of STAT signaling and corresponding migration behaviors.
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Affiliation(s)
- Haowen Yang
- Laboratory of Immunoengineering, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5600MB, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5600 MB, the Netherlands
| | - Nidhi Sinha
- Laboratory of Immunoengineering, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5600MB, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5600 MB, the Netherlands
| | - Ulfert Rand
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany
| | - Hansjörg Hauser
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany
| | - Mario Köster
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany
| | - Tom F A de Greef
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5600 MB, the Netherlands; Computational Biology Group, Department of Biomedical Engineering, Eindhoven University of Technology, 5600MB, Eindhoven, the Netherlands
| | - Jurjen Tel
- Laboratory of Immunoengineering, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5600MB, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5600 MB, the Netherlands.
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Han S, Liu ZQ, Chung DC, Paul MS, Garcia-Batres CR, Sayad A, Elford AR, Gold MJ, Grimshaw N, Ohashi PS. Overproduction of IFNγ by Cbl-b-Deficient CD8+ T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity. Cancer Immunol Res 2022; 10:437-452. [PMID: 35181779 PMCID: PMC9662906 DOI: 10.1158/2326-6066.cir-20-0973] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 11/22/2021] [Accepted: 02/15/2022] [Indexed: 01/07/2023]
Abstract
Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8+ T-cell resistance to Treg-mediated suppression to enhance antitumor immunity. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine signaling and cellular proliferation. We showed that the hypersecretion of IFNγ by Cbl-b-deficient CD8+ T cells selectively attenuated CD8+ T-cell suppression by Tregs. Although IFNγ production by Cbl-b-deficient T cells contributed to phenotypic alterations in Tregs, the cytokine did not attenuate the suppressive function of Tregs. Instead, IFNγ had a profound effect on CD8+ T cells by directly upregulating interferon-stimulated genes and modulating T-cell activation. In murine models of adoptive T-cell therapy, Cbl-b-deficient T cells elicited superior antitumor immune response. Furthermore, Cbl-b-deficient CD8+ T cells were less susceptible to suppression by Tregs in the tumor through the effects of IFNγ. Collectively, this study demonstrates that the hypersecretion of IFNγ serves as a key mechanism by which Cbl-b-deficient CD8+ T cells are rendered resistant to Tregs. See related Spotlight by Wolf and Baier, p. 370.
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Affiliation(s)
- SeongJun Han
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
| | - Zhe Qi Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
| | - Douglas C. Chung
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
| | - Michael St. Paul
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada
| | | | - Azin Sayad
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Alisha R. Elford
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Matthew J. Gold
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Natasha Grimshaw
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada.,Corresponding Author: Pamela S. Ohashi, Princess Margaret Cancer Centre, 610 University Avenue, 9-406, Toronto ON M5G 2M9, Canada. Phone: 416-946-4501 ×3689; E-mail:
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Bamias G, Pizarro TT, Cominelli F. Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease. Inflamm Bowel Dis 2022; 28:337-349. [PMID: 34904152 PMCID: PMC8919810 DOI: 10.1093/ibd/izab251] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Indexed: 02/06/2023]
Abstract
Intestinal fibrosis is a late-stage phenotype of inflammatory bowel disease (IBD), which underlies most of the long-term complications and surgical interventions in patients, particularly those with Crohn's disease. Despite these issues, antifibrotic therapies are still scarce, mainly due to the current lack of understanding concerning the pathogenetic mechanisms that mediate fibrogenesis in patients with chronic intestinal inflammation. In the current review, we summarize recent evidence regarding the cellular and molecular factors of innate and adaptive immunity that are considered critical for the initiation and amplification of extracellular matrix deposition and stricture formation. We focus on the role of cytokines by dissecting the pro- vs antifibrotic components of the immune response, while taking into consideration their temporal association to the progressive stages of the natural history of IBD. We critically present evidence from animal models of intestinal fibrosis and analyze inflammation-fibrosis interactions that occur under such experimental scenarios. In addition, we comment on recent findings from large-scale, single-cell profiling of fibrosis-relevant populations in IBD patients. Based on such evidence, we propose future potential targets for antifibrotic therapies to treat patients with IBD.
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Affiliation(s)
- Giorgos Bamias
- Gastrointestinal Unit, Third Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Theresa T Pizarro
- Departments of Pathology and Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Fabio Cominelli
- Departments of Pathology and Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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43
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Luzina IG, Rus V, Lockatell V, Courneya JP, Hampton BS, Fishelevich R, Misharin AV, Todd NW, Badea TC, Rus H, Atamas SP. Regulator of Cell Cycle Protein (RGCC/RGC-32) Protects against Pulmonary Fibrosis. Am J Respir Cell Mol Biol 2022; 66:146-157. [PMID: 34668840 PMCID: PMC8845131 DOI: 10.1165/rcmb.2021-0022oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Some previous studies in tissue fibrosis have suggested a profibrotic contribution from elevated expression of a protein termed either RGCC (regulator of cell cycle) or RGC-32 (response gene to complement 32 protein). Our analysis of public gene expression datasets, by contrast, revealed a consistent decrease in RGCC mRNA levels in association with pulmonary fibrosis. Consistent with this observation, we found that stimulating primary adult human lung fibroblasts with transforming growth factor (TGF)-β in cell cultures elevated collagen expression and simultaneously attenuated RGCC mRNA and protein levels. Moreover, overexpression of RGCC in cultured lung fibroblasts attenuated the stimulating effect of TGF-β on collagen levels. Similar to humans with pulmonary fibrosis, the levels of RGCC were also decreased in vivo in lung tissues of wild-type mice challenged with bleomycin in both acute and chronic models. Mice with constitutive RGCC gene deletion accumulated more collagen in their lungs in response to chronic bleomycin challenge than did wild-type mice. RNA-Seq analyses of lung fibroblasts revealed that RGCC overexpression alone had a modest transcriptomic effect, but in combination with TGF-β stimulation, induced notable transcriptomic changes that negated the effects of TGF-β, including on extracellular matrix-related genes. At the level of intracellular signaling, RGCC overexpression delayed early TGF-β-induced Smad2/3 phosphorylation, elevated the expression of total and phosphorylated antifibrotic mediator STAT1, and attenuated the expression of a profibrotic mediator STAT3. We conclude that RGCC plays a protective role in pulmonary fibrosis and that its decline permits collagen accumulation. Restoration of RGCC expression may have therapeutic potential in pulmonary fibrosis.
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Affiliation(s)
- Irina G. Luzina
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Violeta Rus
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Virginia Lockatell
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Jean-Paul Courneya
- Health Sciences and Human Services Library, University of Maryland–Baltimore, Baltimore, Maryland
| | | | - Rita Fishelevich
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Alexander V. Misharin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, Illinois
| | - Nevins W. Todd
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Tudor C. Badea
- Retinal Circuits Development and Genetics Unit, National Eye Institute, Bethesda, Maryland; and,Faculty of Medicine, Research and Development Institute, Transilvania University of Brașov, Brașov, Romania
| | - Horea Rus
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
| | - Sergei P. Atamas
- University of Maryland School of Medicine, Baltimore, Maryland;,Baltimore VA Medical Center, Baltimore, Maryland
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Vesicular IFN-γ as a cooperative attacker to enhance anti-cancer effect of 5-fluorouracil via thymidine phosphorylase upregulation and tumor microenvironment normalization. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 40:102501. [PMID: 34843983 DOI: 10.1016/j.nano.2021.102501] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 10/15/2021] [Accepted: 11/05/2021] [Indexed: 12/21/2022]
Abstract
On the basis of immuno-modulating effect and upregulating the activity of thymidine phosphorylase (TP), interferon-γ (IFN-γ) as a cooperative attacker was explored to enhance the anticancer activity of 5-fluorouracil (5-FU). We designed and prepared a self-assembled nano-vesicular system IFN-γ-EDP formulated by amphiphilic poly((polyethylene glycol)(dodecylphosphoethanolamine)phosphazene) (EDP) to entrap IFN-γ in the hydrophilic cavity. The IFN-γ-EDP vesicles allowed IFN-γ to accumulate at the tumor site and be taken up by tumor cells, resulting in significantly upregulated expression level of TP, distinct inhibition of cell growth, more cellular apoptosis and more serious cell cycle arrest when administrated combined with 5-FU. Moreover, IFN-γ-EDP could normalize the tumor microenvironment by enhancing the CD4+ and CD8+ T cell populations, promoting the IL-12 secretion and suppressing the IL-10 secretion in tumor. As a consequence, the combination therapy of IFN-γ-EDP with 5-FU achieved remarkably enhanced tumor inhibition rate of 56.9% against CT26 colorectal cancer.
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Tamura Y, Tsutsumi S, Miyazono K, Koinuma D. PolyI:C attenuates transforming growth factor-β signaling to induce cytostasis of surrounding cells by secreted factors in triple-negative breast cancer. Cancer Sci 2021; 113:940-949. [PMID: 34897916 PMCID: PMC8898727 DOI: 10.1111/cas.15241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 12/04/2021] [Accepted: 12/07/2021] [Indexed: 12/11/2022] Open
Abstract
The activation of RIG‐I‐like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand‐mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)‐β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple‐negative breast cancer cells (TNBC) attenuates transforming growth factor‐β (TGF‐β) signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF‐β signaling by RLR ligands with respect to IFN‐β‐mediated tumor suppression are not well characterized. This study showed that transfection of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN‐β, which inhibits the growth of the surrounding cancer cells. In addition, IFN‐β‐induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3. Constitutively active Smad3 suppresses IFN‐β expression through the alleviation of IFN regulatory factor 3 binding to the canonical target genes, as suggested by ChIP sequencing analysis. Based on these findings, a new facet of the protumorigenic function of TGF‐β that suppresses IFN‐β expression is suggested when RLR‐mediated cancer treatment is used in TNBC.
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Affiliation(s)
- Yusuke Tamura
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shuichi Tsutsumi
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Kohei Miyazono
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daizo Koinuma
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives. Int J Mol Sci 2021; 22:ijms222111748. [PMID: 34769176 PMCID: PMC8584003 DOI: 10.3390/ijms222111748] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 01/10/2023] Open
Abstract
Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFβ or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFβ-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use.
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Wang J, Xu Z, Wang Z, Du G, Lun L. TGF-beta signaling in cancer radiotherapy. Cytokine 2021; 148:155709. [PMID: 34597918 DOI: 10.1016/j.cyto.2021.155709] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022]
Abstract
Transforming growth factor beta (TGF-β) plays key roles in regulating cellular proliferation and maintaining tissue homeostasis. TGF-β exerts tumor-suppressive effects in the early stages of carcinogenesis, but it also plays tumor-promoting roles in established tumors. Additionally, it plays a critical role in cancer radiotherapy. TGF-β expression or activation increases in irradiated tissues, and studies have shown that TGF-β plays dual roles in cancer radiosensitivity and is involved in ionizing radiation-induced fibrosis in different tumor microenvironments (TMEs). Furthermore, TGF-β promotes radioresistance by inducing the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs), suppresses the immune system and facilitates cancer resistance. In particular, the links between TGF-β and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis play a critical role in cancer therapeutic resistance. Growing evidence has shown that TGF-β acts as a radiation protection agent, leading to heightened interest in using TGF-β as a therapeutic target. The future of anti-TGF-β signaling therapy for numerous diseases appears bright, and the outlook for the use of TGF-β inhibitors in cancer radiotherapy as TME-targeting agents is promising.
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Affiliation(s)
- Juan Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Zhonghang Xu
- Department of Gastrointestinal Colorectal and Anal Surgery, The China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Zhe Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Guoqiang Du
- Department of Otolaryngology Head and Neck Surgery, Qingdao Municipal Hospital (Group), Qingdao 266071, Shandong, China.
| | - Limin Lun
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China.
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Chang CJ, Lin CF, Chen BC, Lin PY, Chen CL. SHP2: The protein tyrosine phosphatase involved in chronic pulmonary inflammation and fibrosis. IUBMB Life 2021; 74:131-142. [PMID: 34590785 DOI: 10.1002/iub.2559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/24/2021] [Accepted: 09/11/2021] [Indexed: 12/19/2022]
Abstract
Chronic respiratory diseases (CRDs), including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), lung cancer, and asthma, are significant global health problems due to their prevalence and rising incidence. The roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) in controlling tyrosine phosphorylation of targeting proteins modulate multiple physiological cellular responses and contribute to the pathogenesis of CRDs. Src homology-2 domain-containing PTP2 (SHP2) plays a pivotal role in modulating downstream growth factor receptor signaling and cytoplasmic PTKs, including MAPK/ERK, PI3K/AKT, and JAK/STAT pathways, to regulate cell survival and proliferation. In addition, SHP2 mutation and activation are commonly implicated in tumorigenesis. However, little is known about SHP2 in chronic pulmonary inflammation and fibrosis. This review discusses the potential involvement of SHP2 deregulation in chronic pulmonary inflammation and fibrosis, as well as the therapeutic effects of targeting SHP2 in CRDs.
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Affiliation(s)
- Chun-Jung Chang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chiou-Feng Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Bing-Chang Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pei-Yun Lin
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chia-Ling Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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Okutomo K, Fujino N, Yamada M, Saito T, Ono Y, Okada Y, Ichinose M, Sugiura H. Increased LHX9 expression in alveolar epithelial type 2 cells of patients with chronic obstructive pulmonary disease. Respir Investig 2021; 60:119-128. [PMID: 34548271 DOI: 10.1016/j.resinv.2021.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Alveolar epithelial type 2 (AT2) cells serve as stem cells in alveolar epithelium and are assumed to lose their stem cell function in the lungs of chronic obstructive pulmonary disease (COPD). Although we previously reported that LHX9 mRNA expression was up-regulated in AT2 cells of COPD lung tissues, it is yet to be elucidated how LHX9 is associated with the vulnerability of AT2 cells in COPD. METHODS AT2 cells were isolated from lung tissues of 10 non-COPD subjects and 11 COPD patients. LHX9 mRNA expression was determined by quantitative RT-PCR. To identify up-stream molecules, an alveolar epithelial cell line A549 was exposed to pro-inflammatory cytokines in vitro. siRNA-mediated Lhx9 knockdown was performed to determine how Lhx9 affected the cellular viability and the cell-division cycle. RESULTS LHX9 mRNA expression was increased in AT2 cells from COPD lung tissues, compared to those from non-COPD tissues. The airflow obstruction was independently correlated with the increase in LHX9 expression. Among several pro-inflammatory cytokines, interferon-γ was a strong inducer of LHX9 expression in A549 cells. Lhx9 was involved in the increased susceptibility to serum starvation-induced death of A549 cells. CONCLUSIONS Our data suggest that IFN-γ predominantly increases the LHX9 expression which enhances the susceptibility to cell death. Considering the independent association of the increased LHX9 expression in AT2 cells with airflow obstruction, the IFN-γ-Lhx9 axis might contribute to the vulnerability of AT2 cells in the lungs of COPD patients.
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Affiliation(s)
- Koji Okutomo
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan
| | - Naoya Fujino
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan.
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan
| | - Takuya Saito
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan
| | - Yoshinao Ono
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 980 8575, Japan
| | | | - Hisatoshi Sugiura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 980 8574, Japan
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Marine T, Marielle S, Graziella M, Fabio RMV. Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner. J Neuromuscul Dis 2021; 9:1-23. [PMID: 34542080 PMCID: PMC8842758 DOI: 10.3233/jnd-210737] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle’s capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated.
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Affiliation(s)
- Theret Marine
- School of Biomedical Engineering, Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada
| | - Saclier Marielle
- Department of Biosciences, University of Milan, via Celoria, Milan, Italy
| | - Messina Graziella
- Department of Biosciences, University of Milan, via Celoria, Milan, Italy
| | - Rossi M V Fabio
- School of Biomedical Engineering, Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada
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