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Zhang Y, Zhou Z, Zhang Z, Liu Y, Ji W, Wang J, Wang K, Li Q. Lentinan mitigates ulcerative colitis via the IL-22 pathway to repair the compromised mucosal barrier and enhance antimicrobial defense. Int J Biol Macromol 2025; 307:141784. [PMID: 40054799 DOI: 10.1016/j.ijbiomac.2025.141784] [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: 11/04/2024] [Revised: 02/15/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
Ulcerative colitis (UC) involves chronic, complex pathology of the intestinal mucosa. Current treatments are limited in efficacy and associated with adverse effects, highlighting the urgent need for improved therapeutic options. Lentinan (LNT), a polysaccharide drug commonly used in clinical immune modulation therapies, shows potential for UC treatment, though its specific targets and mechanisms remain unclear. In this study, LNT administration effectively mitigated DSS-induced colitis in mice, enhanced mucosal barrier function and antimicrobial defense. Specifically, LNT modulated the balance between tissue-resident and infiltrating macrophages, thereby improving pathogen clearance and enhancing the immunological barrier. Notably, we identified a novel effect of LNT in regulating the macrophage Dectin-1-ILC3 axis to increase IL-22 secretion. This led to the modulation of epithelial O-glycan fucosylation, antimicrobial peptides, and epithelial stem cells, thereby strengthening antimicrobial defenses and the physicochemical barrier. Neutralization with anti-IL-22 antibodies diminished the therapeutic effect of LNT in UC, underscoring the critical role of IL-22 in LNT-mediated treatment. Overall, this study highlights the potential of LNT as a novel therapeutic agent for UC, offering new insights into its molecular mechanisms and clinical application.
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Affiliation(s)
- Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, China
| | - Zhihong Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China
| | - Zeming Zhang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, China
| | - Yan Liu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, China
| | - Wenting Ji
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China
| | - Jinglin Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, China.
| | - Kaiping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, China.
| | - Qiang Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, China.
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Liu C, Yang L, Wang Z, Zhu H, Luo Q, Wu D, Wang T, Hu M, Wang C, Shao J. Qi-Huang decoction alleviates DSS-induced colitis with Candida albicans dysbiosis by enhancing innate immune response through Dectin-1-associated signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156613. [PMID: 40056633 DOI: 10.1016/j.phymed.2025.156613] [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: 10/27/2024] [Revised: 01/21/2025] [Accepted: 03/04/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract. Candida albicans, a common commensal fungus in the human gut, has been increasingly implicated in UC pathogenesis. Qi-Huang decoction (QHD), a traditional Chinese herbal formula known for its spleen-invigorating and purgative properties, is commonly used to restore gastrointestinal function. PURPOSE This study investigates the therapeutic potential of QHD in treating colitis exacerbated by C. albicans and explores the underlying mechanisms of action. METHODS A mouse model of colitis was induced using dextran sulfate sodium combined with gavage of C. albicans. Following QHD treatment, colitis severity was evaluated by measuring survival rate, body weight, disease activity index, colon length, and fungal burden, and through histopathological analysis using hematoxylin-eosin staining. The expression of proinflammatory genes IL-1β and TNF-α was quantified, alongside protein levels of key molecules involved in Dectin-1 signaling, including Syk, CARD-9, NLRP-3, Raf-1, and NF-κB. Barrier integrity markers, such as Occludin and Claudin-1, were also examined. To further elucidate QHD's mechanisms, Dectin-1 was inhibited using laminarin. In vitro experiments assessed QHD's antifungal activity against three Candida strains through microdilution, spot assays, and time-kill tests. RAW 264.7 macrophages were employed to study the exposure of fungal cell wall β-glucan and subsequent phagocytosis. Molecular docking simulations predicted interactions between QHD's active compounds and the Dectin-1 receptor. RESULTS QHD significantly mitigated colitis severity and reduced fungal burden in vivo. QHD enhanced β-glucan exposure on the fungal cell wall, thereby stimulating phagocytosis by RAW264.7 macrophages. QHD effectively activated Dectin-1-mediated signaling pathways and increased proinflammatory levels in RAW 264.7 cells. In colitis mice, QHD treatment markedly reduced inflammation and Dectin-1 signaling following fungal clearance. However, Dectin-1 inhibition with LAM neutralized QHD's therapeutic effects, highlighting the pathway's importance in mediating QHD's efficacy. Interestingly, QHD alone elevated Dectin-1, NF-κB, TGF-β, and IL-10 levels, whereas reduced IL-1β and TNF-α expression, suggesting a dual modulatory role in inflammation. Molecular docking confirmed a potential direct interaction between QHD's bioactive components and the Dectin-1 receptor. CONCLUSION QHD demonstrates promising therapeutic potential for managing Candida colitis by modulating immune responses and targeting Dectin-1 signaling pathways in clinical settings.
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Affiliation(s)
- Chengcheng Liu
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Liu Yang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Zixu Wang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Hanyu Zhu
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Qinai Luo
- Department of Pathology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University o Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Daqiang Wu
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China; Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Tianming Wang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China; Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Min Hu
- Department of Pathology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University o Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China.
| | - Changzhong Wang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China; Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China
| | - Jing Shao
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, 433 Room, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China; Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Zhijing Building, 350 Longzihu Road, Xinzhan District, Hefei 230012, Anhui, PR China.
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Li T, Wu X, Li X, Chen M. Cancer-associated fungi: An emerging powerful player in cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189287. [PMID: 39971202 DOI: 10.1016/j.bbcan.2025.189287] [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: 04/30/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
The role of the human microbiome in cancer has been extensively studied, focusing mainly on bacteria-host interactions and their impact on tumor development and treatment response. However, fungi, an immune-active component of the human microbiome, have received less attention regarding their roles in cancer. Recent studies have identified the widespread and specific colonization and distribution of fungi in multiple sites in patients across various cancer types. Importantly, host-fungal immune interactions significantly influence immune regulation within the tumor microenvironment. The rapid advancement of immune-checkpoint blockade (ICB)-based cancer immunotherapy creates an urgent need for effective biomarkers and synergistic therapeutic targets. Cancer-associated fungi and their associated antifungal immunity demonstrate significant potential and efficacy in enhancing cancer immunotherapy. This review summarizes and discusses the growing evidence of the functions and mechanisms of commensal and pathogenic cancer-associated fungi in cancer immunotherapy. Additionally, we emphasize the potential of fungi as predictive biomarkers and therapeutic targets in cancer immunotherapy.
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Affiliation(s)
- Tianhang Li
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China; Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China.
| | - Xiangyu Wu
- Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiangyang Li
- Department of Gastrointestinal Tumor Surgery, Nanjing Tianyinshan Hospital, Affiliated Hospital of China Pharmaceutical University, Nanjing, China.
| | - Ming Chen
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China; Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China.
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McFarlin BK, Curtis JH, Vingren JL, Hill DW, Bridgeman EA. Discovery of Innate Immune Response mRNAs That Are Impacted by Structure-Specific Oral Baker's Yeast Beta Glucan Consumption. BIOTECH 2025; 14:4. [PMID: 39846553 PMCID: PMC11755543 DOI: 10.3390/biotech14010004] [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: 10/21/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/24/2025] Open
Abstract
The study of nutritional compounds with the potential to train the innate immune response has implications for human health. The objective of the current study was to discover by what means 6 weeks of oral baker's yeast beta glucan (BYBG) supplementation altered the mRNA expression of genes that reflect innate immune training in the absence of a physical stressor. Nineteen adults were randomly assigned to either a Wellmune® BYBG or Placebo for 6 weeks. BYBG uniquely altered the expression of 40 mRNAs associated with Dectin-1 and trained innate immunity, the innate immune response, the pathogen-associated (PAMP) and damage-associated molecular pattern (DAMP), and the inflammatory response. The observed changes were classified as immune training rather than immune priming due to the progressive increase in the expression of myeloid immune-associated mRNA. Combined with the findings of previous research, the findings of the present study support the claim that oral BYBG supplementation may be associated with trained innate immunity during resting homeostasis. Further, the key findings associated with BYBG may reflect improved responsiveness to future infection (exogenous) and/or sterile-inflammatory (endogenous) challenge.
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Affiliation(s)
- Brian K. McFarlin
- Applied Physiology Laboratory, University of North Texas, Denton, TX 76203, USA; (J.H.C.); (J.L.V.); (D.W.H.)
- Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
| | - John H. Curtis
- Applied Physiology Laboratory, University of North Texas, Denton, TX 76203, USA; (J.H.C.); (J.L.V.); (D.W.H.)
| | - Jakob L. Vingren
- Applied Physiology Laboratory, University of North Texas, Denton, TX 76203, USA; (J.H.C.); (J.L.V.); (D.W.H.)
- Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
| | - David W. Hill
- Applied Physiology Laboratory, University of North Texas, Denton, TX 76203, USA; (J.H.C.); (J.L.V.); (D.W.H.)
| | - Elizabeth A. Bridgeman
- Applied Physiology Laboratory, University of North Texas, Denton, TX 76203, USA; (J.H.C.); (J.L.V.); (D.W.H.)
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Guo S, Zhang Q, Guo Y, Yin X, Zhang P, Mao T, Tian Z, Li X. The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. Front Immunol 2025; 15:1497026. [PMID: 39850880 PMCID: PMC11754255 DOI: 10.3389/fimmu.2024.1497026] [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: 09/16/2024] [Accepted: 12/11/2024] [Indexed: 01/25/2025] Open
Abstract
CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Ni W, Li Y, Feng J, Liu B, Yuan H, Tai G, Bi H. Therapeutic Efficacy and Underlying Mechanisms of a Mannoglucan from Hirsutella sinensis Mycelium on Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease in Mice: Modulation of the Intestinal Barrier, Oxidative Stress and Gut Microbiota. Int J Mol Sci 2024; 25:13100. [PMID: 39684811 DOI: 10.3390/ijms252313100] [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: 11/18/2024] [Revised: 12/01/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Hirsutella sinensis (H. sinensis), a non-sexual form of the valuable Chinese medicinal herb, demonstrates various biological activities, such as immune modulation and antioxidative capabilities. Nonetheless, the effects of bioactive polysaccharides derived from H. sinensis on colitis have yet to be investigated. In our prior research, we extracted a mannoglucan (HSWP-1d) from H. sinensis and found that it attenuates TGF-β1-induced epithelial-mesenchymal transition. The present study investigated the protective effects of HSWP-1d against colitis induced by dextran sulfate sodium (DSS) in mice. The results demonstrate that HSWP-1d effectively ameliorates symptoms of colitis and preserves the intestinal barrier's stability by enhancing the expression of tight junction proteins. The administration of HSWP-1d results in a reduction in oxidative stress through the augmentation of antioxidative enzyme activities, concomitant with the suppression of oxidative product generation. Simultaneously, HSWP-1d reduced the levels of pro-inflammatory cytokines while elevating the levels of anti-inflammatory cytokines, effectively mitigating the inflammatory response. Furthermore, HSWP-1d influences and alters short-chain-fatty-acid (SCFA) levels, thereby enhancing the intestinal microenvironment. In conclusion, HSWP-1d contributes to intestinal well-being and holds potential as both a therapeutic choice and a supplier of essential nutrients for the amelioration of colitis.
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Affiliation(s)
- Weihua Ni
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Yu Li
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Jingyue Feng
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Boxuan Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Hongyan Yuan
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Guixiang Tai
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Hongtao Bi
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, CAS, 23 Xinning Road, Xining 810008, China
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Yang Y, Qiao Y, Liu G, Yi G, Liu H, Zhang T, Tong M. Protective effect of a newly probiotic Lactobacillus reuteri LY2-2 on DSS-induced colitis. Eur J Nutr 2024; 64:5. [PMID: 39546032 DOI: 10.1007/s00394-024-03535-3] [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: 05/15/2024] [Accepted: 11/01/2024] [Indexed: 11/17/2024]
Abstract
PURPOSE This study aimed to investigate the role of a newly isolated strain L.reuteri LY2-2 in colitis in mice and explored the underlying mechanisms. METHODS L. REUTERI LY2-2 was orally administered to mice with dextran sulfate sodium (DSS)-induced colitis. 5-Aminosalicylic acid (5-ASA) treatment was used as the drug control. RESULTS The results showed that the disease severity of colitis mice was significantly alleviated. The intestinal inflammation was restricted by synergistically reducing pro-inflammatory cytokines, inhibiting TLR4-NF-κB signaling, restoring the abnormal immune response, and enhancing intestinal barrier function. Of note, L.reuteri LY2-2 showed great potential in modulating macrophages polarization in colonic tissues. Moreover, the gut dysbiosis was improved. The potentially pro-inflammatory pathogenic bacteria such as Helicobacter and Romboutsia decreased and the probiotics including L.rhamnosus and L.plantarum increased. Interestingly, the above pathological indexes in the L.reuteri LY2-2 group were better than those in the 5-ASA group. CONCLUSION L.reuteri LY2-2 had a better protective effect on DSS-induced colitis via its anti-inflammatory and microbiota-balancing properties, which supports the potential value of this probiotic against colitis. These results contribute to product development of functional probiotics for colitis and provide valuable insights for their mechanisms of biological function to affect human health status.
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Affiliation(s)
- Yong Yang
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, 030001, China
| | - Yuyu Qiao
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, 030001, China
| | - Ge Liu
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, 030001, China
| | - Gaoqin Yi
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, 030001, China
| | - Hongli Liu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China
| | - Ting Zhang
- Department of Ruminant Nutrition, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, 130112, China.
| | - Mingwei Tong
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China.
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, 030001, China.
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Liang W, Zhang W, Tian J, Zhang X, Lv X, Qu A, Chen J, Wu Z. Advances in carbohydrate-based nanoparticles for targeted therapy of inflammatory bowel diseases: A review. Int J Biol Macromol 2024; 281:136392. [PMID: 39423983 DOI: 10.1016/j.ijbiomac.2024.136392] [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: 05/18/2024] [Revised: 09/13/2024] [Accepted: 10/05/2024] [Indexed: 10/21/2024]
Abstract
The incidence of inflammatory bowel disease (IBD), a chronic gastrointestinal disorder, is rapidly increasing worldwide. Unfortunately, the current therapies for IBD are often hindered by premature drug release and undesirable side effects. With the advancement of nanotechnology, the innovative targeted nanotherapeutics are explored to ensure the accurate delivery of drugs to specific sites in the colon, thereby reducing side effects and improving the efficacy of oral administration. The emphasis of this review is to summarize the potential pathogenesis of IBD and highlight recent breakthroughs in carbohydrate-based nanoparticles for IBD treatment, including their construction, release mechanism, potential targeting ability, and their therapeutic efficacy. Specifically, we summarize the latest knowledge regarding environmental-responsive nano-systems and active targeted nanoparticles. The environmental-responsive drug delivery systems crafted with carbohydrates or other biological macromolecules like chitosan and sodium alginate, exhibit a remarkable capacity to enhance the accumulation of therapeutic drugs in the inflamed regions of the digestive tract. Active targeting strategies improve the specificity and accuracy of oral drug delivery to the colon by modifying carbohydrates such as hyaluronic acid and mannose onto nanocarriers. Finally, we discuss the challenges and provide insight into the future perspectives of colon-targeted delivery systems for IBD treatment.
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Affiliation(s)
- Wenjing Liang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Wen Zhang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China.
| | - Jiayi Tian
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Xinping Zhang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Xinyi Lv
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Ao Qu
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Jinyu Chen
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China
| | - Zijian Wu
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China.
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Yang L, Hu M, Shao J. Integration of Gut Mycobiota and Oxidative Stress to Decipher the Roles of C-Type Lectin Receptors in Inflammatory Bowel Diseases. Immunol Invest 2024; 53:1177-1204. [PMID: 39115960 DOI: 10.1080/08820139.2024.2388164] [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] [Indexed: 08/10/2024]
Abstract
BACKGROUND Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of inflammatory bowel disease (IBD) with rapidly increased incidence worldwide. Although multiple factors contribute to the occurrence and progression of IBD, the role of intestinal fungal species (gut mycobiota) in regulating the severity of these conditions has been increasingly recognized. C-type lectin receptors (CLRs) on hematopoietic cells, including Dectin-1, Dectin-2, Dectin-3, Mincle and DC-SIGN, are a group of pattern recognition receptors (PRRs) that primarily recognize fungi and mediate defense responses, such as oxidative stress. Recent studies have demonstrated the indispensable role of CLRs in protecting the colon from intestinal inflammation and mucosal damage. METHODS AND RESULTS This review provides a comprehensive overview of the role of CLRs in the pathogenesis of IBD. Given the significant impact of mycobiota and oxidative stress in IBD, this review also discusses recent advancements in understanding how these factors exacerbate or ameliorate IBD. Furthermore, the latest developments in CLR-guided IBD therapy are examined to highlight the modulation of CLRs in fungal recognition and oxidative burst during the IBD process. CONCLUSION This review emphasizes the importance of CLRs in IBD, offering new perspectives on the etiology and therapeutic approaches for this disease.
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Affiliation(s)
- Liu Yang
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui 230012, P. R. China
| | - Min Hu
- Department of pathology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui, P. R. China
| | - Jing Shao
- Laboratory of Anti-infection and Immunity, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui 230012, P. R. China
- Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, Anhui, P. R. China
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Li Y, Huang M, Cardinale S, Su Y, Peters DE, Slusher BS, Zhu X. Dectin-1 as a therapeutic target for inflammatory bowel disease. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:237-264. [PMID: 39521602 PMCID: PMC11733682 DOI: 10.1016/bs.apha.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Inflammatory bowel disease (IBD) encompasses chronic inflammatory conditions of the distal gastrointestinal tract, including Crohn's disease and ulcerative colitis. This chapter explores the potential of Dendritic cell-associated C-type lectin-1 (Dectin-1), a pattern recognition receptor, as a therapeutic target for IBD. We delve into the multifaceted roles of Dectin-1 in immune response modulation, focusing on its interactions with the gut microbiota and immune system. Key sections include an examination of intestinal dysbiosis and its impact on IBD, highlighting the critical role of fungal dysbiosis and immune responses mediated by Dectin-1. The chapter discusses the dual functions of Dectin-1 in maintaining gut homeostasis and its contribution to disease pathogenesis through interactions with the gut's fungal community. Furthermore, the genetic and molecular mechanisms underpinning Dectin-1's role in IBD susceptibility are explored, alongside its signaling pathways and their effects on immune modulation. We also present therapeutic strategies targeting Dectin-1, including innovative drug delivery systems that leverage its natural binding affinity for β-glucans, enhancing targeted delivery to inflamed tissues. The chapter underscores the potential of dietary modulation of Dectin-1 pathways to restore gut microbiota balance and suggests future research directions to fully exploit Dectin-1's therapeutic potential in managing IBD. By elucidating the complex interplay between Dectin-1 and the gut microbiota, this chapter provides insights into novel therapeutic approaches aimed at mitigating IBD symptoms and improving patient outcomes.
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Affiliation(s)
- Yannan Li
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Meixiang Huang
- Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Santiago Cardinale
- Department of Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Yu Su
- Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Diane E Peters
- Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Barbara S Slusher
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Xiaolei Zhu
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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11
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Han H, Zhang G, Zhang X, Zhao Q. Nrf2-mediated ferroptosis inhibition: a novel approach for managing inflammatory diseases. Inflammopharmacology 2024; 32:2961-2986. [PMID: 39126567 DOI: 10.1007/s10787-024-01519-7] [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: 06/01/2024] [Accepted: 06/28/2024] [Indexed: 08/12/2024]
Abstract
Inflammatory diseases, including psoriasis, atherosclerosis, rheumatoid arthritis, and ulcerative colitis, are characterized by persistent inflammation. Moreover, the existing treatments for inflammatory diseases only provide temporary relief by controlling symptoms, and treatments of unstable and expensive. Therefore, new therapeutic solutions are urgently needed to address the underlying causes or symptoms of inflammatory diseases. Inflammation frequently coincides with a high level of (reactive oxygen species) ROS activation, serving as a fundamental element in numerous physiological and pathological phenotypes that can result in serious harm to the organism. Given its pivotal role in inflammation, oxidative stress, and ferroptosis, ROS represents a focal node for investigating the (nuclear factor E2-related factor 2) Nrf2 pathway and ferroptosis, both of which are intricately linked to ROS. Ferroptosis is mainly triggered by oxidative stress and involves iron-dependent lipid peroxidation. The transcription factor Nrf2 targets several genes within the ferroptosis pathway. Recent studies have shown that Nrf2 plays a significant role in three key ferroptosis-related routes, including the synthesis and metabolism of glutathione/glutathione peroxidase 4, iron metabolism, and lipid processes. As a result, ferroptosis-related treatments for inflammatory diseases have attracted much attention. Moreover, drugs targeting Nrf2 can be used to manage inflammatory conditions. This review aimed to assess ferroptosis regulation mechanism and the role of Nrf2 in ferroptosis inhibition. Therefore, this review article may provide the basis for more research regarding the treatment of inflammatory diseases through Nrf2-inhibited ferroptosis.
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Affiliation(s)
- Hang Han
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China
| | - Guojiang Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China
| | - Xiao Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China.
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China.
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12
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Dai C, Li W, Zhang C, Shen X, Wan Z, Deng X, Liu F. Microencapsule delivery systems of functional substances for precision nutrition. ADVANCES IN FOOD AND NUTRITION RESEARCH 2024; 112:199-255. [PMID: 39218503 DOI: 10.1016/bs.afnr.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Microencapsulation, a typical core-shell structure technology, encapsulates functional active ingredients for protection, controlled release, and targeted delivery. In precise nutrition, the focus is on utilizing microcapsule delivery systems for personalized dietary supplements and disease intervention. This chapter outlines the morphological structure of microcapsules, common wall materials, and preparation techniques. It discusses the characteristics of different hydrophilic and lipophilic functional factors and their function as dietary supplements. The role of microencapsulation on the controlled release, odor masking, and enhanced bioavailability of functional factors is explored. Additionally, the application of microcapsule delivery systems in nutritional interventions for diseases like inflammatory bowel disease, alcoholic/fatty liver disease, diabetes, and cancer is introduced in detail. Lastly, the chapter proposes the future developments of anticipation in responsive wall materials for precise nutrition interventions, including both challenges and opportunities.
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Affiliation(s)
- Chenlin Dai
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Wenhan Li
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Chairui Zhang
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Xuelian Shen
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Ziyan Wan
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Xiaofan Deng
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China
| | - Fuguo Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, P.R. China.
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13
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Qing F, Sui L, He W, Chen Y, Xu L, He L, Xiao Q, Guo T, Liu Z. IRF7 Exacerbates Candida albicans Infection by Compromising CD209-Mediated Phagocytosis and Autophagy-Mediated Killing in Macrophages. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1932-1944. [PMID: 38709167 DOI: 10.4049/jimmunol.2300826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/20/2024] [Indexed: 05/07/2024]
Abstract
IFN regulatory factor 7 (IRF7) exerts anti-infective effects by promoting the production of IFNs in various bacterial and viral infections, but its role in highly morbid and fatal Candida albicans infections is unknown. We unexpectedly found that Irf7 gene expression levels were significantly upregulated in tissues or cells after C. albicans infection in humans and mice and that IRF7 actually exacerbates C. albicans infection in mice independent of its classical function in inducing IFNs production. Compared to controls, Irf7-/- mice showed stronger phagocytosis of fungus, upregulation of C-type lectin receptor CD209 expression, and enhanced P53-AMPK-mTOR-mediated autophagic signaling in macrophages after C. albicans infection. The administration of the CD209-neutralizing Ab significantly hindered the phagocytosis of Irf7-/- mouse macrophages, whereas the inhibition of p53 or autophagy impaired the killing function of these macrophages. Thus, IRF7 exacerbates C. albicans infection by compromising the phagocytosis and killing capacity of macrophages via regulating CD209 expression and p53-AMPK-mTOR-mediated autophagy, respectively. This finding reveals a novel function of IRF7 independent of its canonical IFNs production and its unexpected role in enhancing fungal infections, thus providing more specific and effective targets for antifungal therapy.
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Affiliation(s)
- Furong Qing
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
| | - Lina Sui
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
| | - Wenji He
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
- School of Graduate, China Medical University, Shenyang, Liaoning
| | - Yayun Chen
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
- School of Graduate, China Medical University, Shenyang, Liaoning
| | - Li Xu
- Center for Scientific Research, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Liangmei He
- School of Graduate, China Medical University, Shenyang, Liaoning
- Department of Gastroenterology, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qiuxiang Xiao
- School of Graduate, China Medical University, Shenyang, Liaoning
- Department of Pathology, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Tianfu Guo
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
| | - Zhiping Liu
- School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi
- Center for Scientific Research, Gannan Medical University, Ganzhou, Jiangxi, China
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China
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14
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Liao X, Liu J, Guo X, Meng R, Zhang W, Zhou J, Xie X, Zhou H. Origin and Function of Monocytes in Inflammatory Bowel Disease. J Inflamm Res 2024; 17:2897-2914. [PMID: 38764499 PMCID: PMC11100499 DOI: 10.2147/jir.s450801] [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: 11/20/2023] [Accepted: 04/23/2024] [Indexed: 05/21/2024] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disease resulting from the interaction of various factors such as social elements, autoimmunity, genetics, and gut microbiota. Alarmingly, recent epidemiological data points to a surging incidence of IBD, underscoring an urgent imperative: to delineate the intricate mechanisms driving its onset. Such insights are paramount, not only for enhancing our comprehension of IBD pathogenesis but also for refining diagnostic and therapeutic paradigms. Monocytes, significant immune cells derived from the bone marrow, serve as precursors to macrophages (Mφs) and dendritic cells (DCs) in the inflammatory response of IBD. Within the IBD milieu, their role is twofold. On the one hand, monocytes are instrumental in precipitating the disease's progression. On the other hand, their differentiated offsprings, namely moMφs and moDCs, are conspicuously mobilized at inflammatory foci, manifesting either pro-inflammatory or anti-inflammatory actions. The phenotypic spectrum of these effector cells, intriguingly, is modulated by variables such as host genetics and the subtleties of the prevailing inflammatory microenvironment. Notwithstanding their significance, a palpable dearth exists in the literature concerning the roles and mechanisms of monocytes in IBD pathogenesis. This review endeavors to bridge this knowledge gap. It offers an exhaustive exploration of monocytes' origin, their developmental trajectory, and their differentiation dynamics during IBD. Furthermore, it delves into the functional ramifications of monocytes and their differentiated progenies throughout IBD's course. Through this lens, we aspire to furnish novel perspectives into IBD's etiology and potential therapeutic strategies.
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Affiliation(s)
- Xiping Liao
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
- Department of Gastroenterology, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Ji Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China
| | - Xiaolong Guo
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Ruiping Meng
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Wei Zhang
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Jianyun Zhou
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Xia Xie
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
- Department of Gastroenterology, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Hongli Zhou
- Clinical Medical Research Center, the Second Affiliated Hospital, Army Medical University, Chongqing, People’s Republic of China
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15
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Paurević M, Šrajer Gajdošik M, Ribić R. Mannose Ligands for Mannose Receptor Targeting. Int J Mol Sci 2024; 25:1370. [PMID: 38338648 PMCID: PMC10855088 DOI: 10.3390/ijms25031370] [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: 12/14/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.
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Affiliation(s)
- Marija Paurević
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia; (M.P.); (M.Š.G.)
| | - Martina Šrajer Gajdošik
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia; (M.P.); (M.Š.G.)
| | - Rosana Ribić
- Department of Nursing, University Center Varaždin, University North, Jurja Križanića 31b, HR-42000 Varaždin, Croatia
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16
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Zhang J, Tu Y, Wei J, Zheng R, Shao J, Chen Q, Liang G, Ying H, Han X, Shi Q. Dectin1 contributes to hypertensive vascular injury by promoting macrophage infiltration through activating the Syk/NF-κB pathway. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166911. [PMID: 37813169 DOI: 10.1016/j.bbadis.2023.166911] [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: 06/13/2023] [Revised: 09/13/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023]
Abstract
Vascular injury is an early manifestation leading to end-organ damage in hypertension pathogenesis, which involves a macrophage-associated immune response. Dendritic cell-associated C-type lectin-1 (Dectin1) is a pivotal player in regulating inflammation-mediated cardiovascular disease. However, its role in hypertension-induced vascular damage and the underlying mechanisms remain unclear. We hypothesized that Dectin1 might accelerate angiotensin II (Ang II)- or deoxycorticosterone acetate-salt (DOCA-salt)-induced vascular injury through proinflammatory actions in macrophages. Macrophage Dectin1 was upregulated in mouse aortic tissues stimulated with Ang II. In the peripheral blood, Ang II also increased CD11b+F4/80+ macrophages in mice. In our constructed Dectin1 knockout mice, Dectin1 deletion protected against Ang II-induced EB extravasation and aortic wall thickness. Deficiency of Dectin1 or its pharmacological inhibition considerably improved fibrosis and inflammation responses, accompanied by a reduction in M1 macrophage polarization as well as proinflammatory cytokines and chemokines induced by Ang II or DOCA-salt. Through the bone marrow (BM) transplantation assay, these effects were verified in the wild type mice reconstituted with Dectin1-deficient BM cells. Mechanistically, Ang II promoted Dectin1 homodimerization, thereby triggering the spleen tyrosine kinase/nuclear factor kappa B pro-inflammatory cascade to induce the expression of inflammatory factors and chemokines in vivo and in vitro. In conclusion, Dectin1 has an essential role in the pathogenic procedure of Ang II-stimulated or DOCA-salt-induced vascular damage in mice and represents a promising therapeutic target for cardiovascular diseases.
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Affiliation(s)
- Jiajia Zhang
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China; Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou 310013, China
| | - Yu Tu
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China; Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou 310013, China
| | - Jiajia Wei
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China
| | - Ruyi Zheng
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China
| | - Ji Shao
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China
| | - Qinhua Chen
- Key Laboratory of TCM Clinical Pharmacy, Shenzhen Baoan Authentic TCM Therapy Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518101, China
| | - Guang Liang
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China
| | - Huazhong Ying
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China; Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou 310013, China.
| | - Xue Han
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China.
| | - Qiaojuan Shi
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou 310013, China; Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou 310013, China.
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17
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Ji ZZ, Chan MKK, Chan ASW, Leung KT, Jiang X, To KF, Wu Y, Tang PMK. Tumour-associated macrophages: versatile players in the tumour microenvironment. Front Cell Dev Biol 2023; 11:1261749. [PMID: 37965573 PMCID: PMC10641386 DOI: 10.3389/fcell.2023.1261749] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/12/2023] [Indexed: 11/16/2023] Open
Abstract
Tumour-Associated Macrophages (TAMs) are one of the pivotal components of the tumour microenvironment. Their roles in the cancer immunity are complicated, both pro-tumour and anti-cancer activities are reported, including not only angiogenesis, extracellular matrix remodeling, immunosuppression, drug resistance but also phagocytosis and tumour regression. Interestingly, TAMs are highly dynamic and versatile in solid tumours. They show anti-cancer or pro-tumour activities, and interplay between the tumour microenvironment and cancer stem cells and under specific conditions. In addition to the classic M1/M2 phenotypes, a number of novel dedifferentiation phenomena of TAMs are discovered due to the advanced single-cell technology, e.g., macrophage-myofibroblast transition (MMT) and macrophage-neuron transition (MNT). More importantly, emerging information demonstrated the potential of TAMs on cancer immunotherapy, suggesting by the therapeutic efficiency of the checkpoint inhibitors and chimeric antigen receptor engineered cells based on macrophages. Here, we summarized the latest discoveries of TAMs from basic and translational research and discussed their clinical relevance and therapeutic potential for solid cancers.
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Affiliation(s)
- Zoey Zeyuan Ji
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Max Kam-Kwan Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Alex Siu-Wing Chan
- Department of Applied Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Kam-Tong Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Xiaohua Jiang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Yi Wu
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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18
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Kolypetri P, Weiner HL. Monocyte regulation by gut microbial signals. Trends Microbiol 2023; 31:1044-1057. [PMID: 37271658 PMCID: PMC10524398 DOI: 10.1016/j.tim.2023.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 06/06/2023]
Abstract
Monocytes are innate immune cells that sense environmental changes and participate in the immunoregulation of autoimmune, neurologic, cardiovascular, and metabolic diseases as well as cancer. Recent studies have suggested that the gut microbiome shapes the biology of monocytes via microbial signals at extraintestinal sites. Interestingly, in chronic diseases, communication between microbial signals and monocytes can either promote or inhibit disease activity, suggesting that some of these pathways can be harnessed for clinical therapies. In this review, we discuss the newer concepts of regulation of monocyte homeostasis and function by gut microbial signals during steady state and inflammation. We also highlight the therapeutic potential of microbial signal-based approaches for modulation in the context of various diseases.
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Affiliation(s)
- Panayota Kolypetri
- Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Howard L Weiner
- Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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19
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Yuan J. CCR2: A characteristic chemokine receptor in normal and pathological intestine. Cytokine 2023; 169:156292. [PMID: 37437448 DOI: 10.1016/j.cyto.2023.156292] [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: 05/10/2023] [Revised: 06/25/2023] [Accepted: 07/01/2023] [Indexed: 07/14/2023]
Abstract
C-C motif chemokine receptor 2 (CCR2), together with its ligands, especially C-C motif ligand 2 (CCL2), to which CCR2 has the highest affinity, form a noteworthy signaling pathway in recruiting macrophages for the immune responses among variegated disorders in vivo environment. Scientometric methods are used to analyze intestine-related CCR2 expression. We describe the current knowledge on biological function of CCR2 in physiological intestine in three dimensions, namely its effects on stromal cells, angiogenesis, and remodeling. However, anomalous expression of CCR2 has also been conveyed to correlate with detrimental outcomes in intestine, such as infective colitis, inflammatory bowel disease, carcinogenesis, and colon-related metastasis. In this article, we briefly summarize recent experimental works on CCR2 and its ligands, mostly CCL2, in intestinal-related physiological and pathological states to ravel out their working mechanisms in intestinal diseases.
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Affiliation(s)
- Jin Yuan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
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20
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Yoo D, Whang CH, Hong J, Kim D, Prayogo MC, Son Y, Jung W, Lee S, Lee HS, Jon S. Anti-inflammatory Glycocalyx-Mimicking Nanoparticles for Colitis Treatment: Construction and In Vivo Evaluation. Angew Chem Int Ed Engl 2023; 62:e202304815. [PMID: 37310766 DOI: 10.1002/anie.202304815] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/01/2023] [Accepted: 06/13/2023] [Indexed: 06/14/2023]
Abstract
Common medications for treating inflammatory bowel disease (IBD) have limited therapeutic efficacy and severe adverse effects. This underscores the urgent need for novel therapeutic approaches that can effectively target inflamed sites in the gastrointestinal tract upon oral administration, exerting potent therapeutic efficacy while minimizing systemic effects. Here, we report the construction and in vivo therapeutic evaluation of a library of anti-inflammatory glycocalyx-mimicking nanoparticles (designated GlyNPs) in a mouse model of IBD. The anti-inflammatory GlyNP library was created by attaching bilirubin (BR) to a library of glycopolymers composed of random combinations of the five most naturally abundant sugars. Direct in vivo screening of 31 BR-attached anti-inflammatory GlyNPs via oral administration into mice with acute colitis led to identification of a candidate GlyNP capable of targeting macrophages in the inflamed colon and effectively alleviating colitis symptoms. These findings suggest that the BR-attached GlyNP library can be used as a platform to identify anti-inflammatory nanomedicines for various inflammatory diseases.
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Affiliation(s)
- Dohyun Yoo
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Chang-Hee Whang
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Jungwoo Hong
- Department of Chemistry, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Multiscale Chiral Architectures (CMCA), KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Dohyeon Kim
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Monica Celine Prayogo
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Youngju Son
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Wonsik Jung
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Seojung Lee
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Hee-Seung Lee
- Department of Chemistry, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Multiscale Chiral Architectures (CMCA), KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
| | - Sangyong Jon
- Department of Biological Sciences, Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon, 34141, Republic of Korea
- Center for Precision Bio-Nanomedicine, KAIST, 291 Daehak-ro, Daejeon, 34141, Republic of Korea
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21
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Liu J, Cai J, Fan P, Dong X, Zhang N, Tai J, Cao Y. Salidroside alleviates dextran sulfate sodium-induced colitis in mice by modulating the gut microbiota. Food Funct 2023; 14:7506-7519. [PMID: 37504971 DOI: 10.1039/d3fo01929b] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Dysbiosis causes continuous progress of inflammatory bowel disease (IBD). Herein, we aim to explore whether Salidroside (Sal), which is a major glycoside extracted from Rhodiola rosea L., could ameliorate dextran sulfate sodium (DSS)-induced colitis by modulating the microbiota. Results showed that oral treatment with 15 mg kg-1 of Sal inhibited DSS-induced colitis in mice as evidenced by colon length, histological analysis, disease activity index (DAI) score, and the proportion and number of macrophages in the intestine. The gut microbiota of colitic mice was also partly restored by Sal. A fecal microbiota transplantation (FMT) study was designed to verify the causality. Compared with DSS-treated mice, FM from the Sal-treated donor mice significantly mitigated the symptoms of colitic mice, including reducing the DAI score, alleviating tissue damage, boosting the expression of mucin protein (mucin-2) and tight junction (TJ) proteins (occludin and zonula occludens-1 (ZO-1), and decreasing M1 macrophages in the gut. It was found that both Sal and FMT affected the structure and abundance of the gut microbiota as reflected by the decreased relative abundance of Turicibacter, Alistipes, Romboutsia and the increased relative abundance of Lactobacillus at the genus level. Moreover, the anti-inflammatory effect of Sal disappeared when the gut microbiota was depleted by antibiotics, demonstrating that Sal alleviated the intestinal inflammation in a gut microbiota-dependent manner. Thus, Sal could be a remarkable candidate as a functional food for colitis.
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Affiliation(s)
- Jiuxi Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, People's Republic of China
| | - Jiapei Cai
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
| | - Peng Fan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
| | - Xue Dong
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
| | - Naisheng Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
| | - Jiandong Tai
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, 130021 Changchun, People's Republic of China.
| | - Yongguo Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China.
- Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 130062 Changchun, People's Republic of China
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22
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Bao MY, Li M, Bu QR, Yang Y, Song H, Wang CZ, Wang TM, Li N. The effect of herbal medicine in innate immunity to Candida albicans. Front Immunol 2023; 14:1096383. [PMID: 37483621 PMCID: PMC10359817 DOI: 10.3389/fimmu.2023.1096383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 03/06/2023] [Indexed: 07/25/2023] Open
Abstract
Candida albicans (C. albicans) is an opportunistic pathogenic fungus that often causes mucosal and systemic infections. Several pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), have been implicated in the host recognition of C. albicans. These PRRs recognize the pathogen-associated molecular patterns (PAMPs) of C. albicans to activate innate immune cells, thereby rapidly inducing various inflammatory responses by activating intracellular signaling cascades. Herbal medicine and its active components deserve priority development due to their low toxicity and high antibacterial, antiviral and antifungal activities. This review discussed the activities of herbal compounds against C. albicans and their related mechanisms, especially their regulatory role on innate immune cells such as neutrophils, macrophages, and dendritic cells (DCs) implicated in C. albicans infections. Our work aims to find new therapeutic drugs and targets to prevent and treat diseases caused by C. albicans infection with the mechanisms by which this fungus interacts with the innate immune response.
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Affiliation(s)
- Meng-Yuan Bao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Ming Li
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Qing-Ru Bu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Yue Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Hang Song
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Chang-Zhong Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Tian-Ming Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ning Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
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23
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Tang C, Sun H, Kadoki M, Han W, Ye X, Makusheva Y, Deng J, Feng B, Qiu D, Tan Y, Wang X, Guo Z, Huang C, Peng S, Chen M, Adachi Y, Ohno N, Trombetta S, Iwakura Y. Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression. Nat Commun 2023; 14:1493. [PMID: 36932082 PMCID: PMC10023663 DOI: 10.1038/s41467-023-37229-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and ApcMin-induced intestinal tumorigenesis are suppressed in Clec7a-/- mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a-/- mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E2 (PGE2) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2) is upregulated. Dectin-1 signaling induces PGE2-synthesizing enzymes and PGE2 suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE2-synthesizing enzyme expression and PGE2 suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE2-IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.
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Affiliation(s)
- Ce Tang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China.
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China.
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan.
| | - Haiyang Sun
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan
| | - Motohiko Kadoki
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan
| | - Wei Han
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan
| | - Xiaoqi Ye
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan
| | - Yulia Makusheva
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan
| | - Jianping Deng
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Bingbing Feng
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Ding Qiu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Ying Tan
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Xinying Wang
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Zehao Guo
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Chanyan Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Sui Peng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, 510080, Guangzhou, Guangdong Province, China
| | - Yoshiyuki Adachi
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan
| | - Naohito Ohno
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan
| | - Sergio Trombetta
- Boehringer Ingelheim USA, 900 Ridgebury Rd, Ridgefield, CT, 06877, USA
| | - Yoichiro Iwakura
- Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda-shi, Chiba, 278-0022, Japan.
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24
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Kuo NR, Hou MC, Chu WC, Yang YY, Huang CC, Li TH, Lee TY, Liu CW, Liao TL, Hsieh SL, Lin HC. Low lymphocyte-to-monocyte ratio, calcitriol level, and CD206 level predict the development of acute-on-chronic liver failure in patients cirrhosis with acute decompensation. J Chin Med Assoc 2023; 86:265-273. [PMID: 36727703 DOI: 10.1097/jcma.0000000000000867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Cirrhosis-related acute-on-chronic liver failure (ACLF) is associated with high morbidity and mortality rates. Prognostic models of ACLF have been developed; however, few studies have focused on the occurrence of ACLF. This study aimed to identify the factors that predict the development of ACLF, hepatic encephalopathy (HE), and infection in patients with cirrhosis. METHODS Patients with cirrhosis were enrolled, and the serum levels of calcitriol, Cluster of Differentiation 26 (CD206), and macrophage-inducible lectin receptor (Mincle) were measured, and lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio were calculated; all the patients were tracked for 6 months. A generalized estimating equation (GEE) was used to assess the factors associated with ACLF development, HE, and infection. The aforementioned model was derived based on immunological markers, and receiver operating characteristic analysis with area under the curve (AUC) was adopted to evaluate accuracy. RESULTS After screening 325 patients with cirrhosis, 65 patients were eligible. In the GEE model, low levels of calcitriol (odds ratio [OR] = 3.259; 95% confidence interval [CI] = 1.118-8.929) and CD206 (OR = 2.666; 95% CI = 1.082-6.567) were associated with the development of ACLF, and the LMR was a protective factor (OR = 0.356; 95% CI = 0.147-0.861). Low calcitriol levels were a risk factor for HE (OR = 3.827) and infection (OR = 2.489). LMR was found to be a protective factor against HE (OR = 0.388). An immunological model for the discrimination of ACLF development within 6 months was proposed, with an AUC of 0.734 (95% CI = 0.598-0.869). CONCLUSION Single and combined immunological markers, including low LMR and low levels of calcitriol and CD206, were promising for early prediction of the development of ACLF, HE, and infection in patients with cirrhosis.
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Affiliation(s)
- Nai-Rong Kuo
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wei-Chi Chu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ying-Ying Yang
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chia-Chang Huang
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, Linkou Chang Guang Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Chih-Wei Liu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tsai-Ling Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
| | - Shie-Liang Hsieh
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC
| | - Han-Chieh Lin
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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25
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Peckert-Maier K, Langguth P, Strack A, Stich L, Mühl-Zürbes P, Kuhnt C, Drassner C, Zinser E, Wrage M, Mattner J, Steinkasserer A, Royzman D, Wild AB. CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation. Front Immunol 2023; 14:1085742. [PMID: 36875129 PMCID: PMC9975560 DOI: 10.3389/fimmu.2023.1085742] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Excessive macrophage (Mφ) activation results in chronic inflammatory responses or autoimmune diseases. Therefore, identification of novel immune checkpoints on Mφ, which contribute to resolution of inflammation, is crucial for the development of new therapeutic agents. Herein, we identify CD83 as a marker for IL-4 stimulated pro-resolving alternatively activated Mφ (AAM). Using a conditional KO mouse (cKO), we show that CD83 is important for the phenotype and function of pro-resolving Mφ. CD83-deletion in IL-4 stimulated Mφ results in decreased levels of inhibitory receptors, such as CD200R and MSR-1, which correlates with a reduced phagocytic capacity. In addition, CD83-deficient Mφ upon IL-4 stimulation, show an altered STAT-6 phosphorylation pattern, which is characterized by reduced pSTAT-6 levels and expression of the target gene Gata3. Concomitantly, functional studies in IL-4 stimulated CD83 KO Mφ reveal an increased production of pro-inflammatory mediators, such as TNF-α, IL-6, CXCL1 and G-CSF. Furthermore, we show that CD83-deficient Mφ have enhanced capacities to stimulate the proliferation of allo-reactive T cells, which was accompanied by reduced frequencies of Tregs. In addition, we show that CD83 expressed by Mφ is important to limit the inflammatory phase using a full-thickness excision wound healing model, since inflammatory transcripts (e.g. Cxcl1, Il6) were increased, whilst resolving transcripts (e.g. Ym1, Cd200r, Msr-1) were decreased in wounds at day 3 after wound infliction, which reflects the CD83 resolving function on Mφ also in vivo. Consequently, this enhanced inflammatory milieu led to an altered tissue reconstitution after wound infliction. Thus, our data provide evidence that CD83 acts as a gatekeeper for the phenotype and function of pro-resolving Mφ.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Pia Langguth
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Astrid Strack
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Christine Kuhnt
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Christina Drassner
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Marius Wrage
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitäts-klinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitäts-klinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
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26
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Hatinguais R, Willment JA, Brown GD. C-type lectin receptors in antifungal immunity: Current knowledge and future developments. Parasite Immunol 2023; 45:e12951. [PMID: 36114607 PMCID: PMC10078331 DOI: 10.1111/pim.12951] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 09/05/2022] [Accepted: 09/12/2022] [Indexed: 01/31/2023]
Abstract
C-type lectin receptors (CLRs) constitute a category of innate immune receptors that play an essential role in the antifungal immune response. For over two decades, scientists have uncovered what are the fungal ligands recognized by CLRs and how these receptors initiate the immune response. Such studies have allowed the identification of genetic polymorphisms in genes encoding for CLRs or for proteins involved in the signalisation cascade they trigger. Nevertheless, our understanding of how these receptors functions and the full extent of their function during the antifungal immune response is still at its infancy. In this review, we summarize some of the main findings about CLRs in antifungal immunity and discuss what the future might hold for the field.
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Affiliation(s)
- Remi Hatinguais
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Janet A Willment
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Gordon D Brown
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
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27
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Hu W, Li P, Zeng N, Tan S. Exploring the hub mechanisms of ischemic stroke based on protein-protein interaction networks related to ischemic stroke and inflammatory bowel disease. Sci Rep 2023; 13:1741. [PMID: 36720935 PMCID: PMC9887582 DOI: 10.1038/s41598-023-27459-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 01/02/2023] [Indexed: 02/01/2023] Open
Abstract
Ischemic stroke is highly concerning because it often leads to severe long-term neurological disability. Among clinical trials, ischemic stroke and inflammatory bowel disease interactions have been increasingly reported in recent years. Therefore, using bioinformatics approaches to explore novel protein interactions between them is of interest. We performed this exploratory analysis by using bioinformatics tools such as string to analyze gene data downloaded from NHGRI-GWAS data related to ischemic stroke and inflammatory bowel disease. We constructed a prospective protein interaction network for ischemic stroke and inflammatory bowel disease, identifying cytokine and interleukin-related signaling pathways, Spliceosome, Ubiquitin-Proteasome System (UPS), Thrombus, and Anticoagulation pathways as the crucial biological mechanisms of the network. Furthermore, we also used data-independent acquisition mass spectrometry (DIA-MS) to detect differential protein expression in eight samples, which also suggested that immune system, signal transduction, and hemostasis-related pathways are key signaling pathways. These findings may provide a basis for understanding the interaction between these two states and exploring possible molecular and therapeutic studies in the future.
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Affiliation(s)
- Wei Hu
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.,Department of Rehabilitation, Xiangya Bo'ai Rehabilitation Hospital, Changsha, 410004, China
| | - Ping Li
- Department of Rehabilitation, Xiangya Bo'ai Rehabilitation Hospital, Changsha, 410004, China
| | - Nianju Zeng
- Department of Rehabilitation, Xiangya Bo'ai Rehabilitation Hospital, Changsha, 410004, China.
| | - Sheng Tan
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
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28
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Wang MX, Luo W, Ye L, Jin LM, Yang B, Zhang QH, Qian JC, Wang Y, Zhang Y, Liang G. Dectin-1 plays a deleterious role in high fat diet-induced NAFLD of mice through enhancing macrophage activation. Acta Pharmacol Sin 2023; 44:120-132. [PMID: 35689091 DOI: 10.1038/s41401-022-00926-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/24/2022] [Indexed: 01/18/2023]
Abstract
The innate immune response and inflammation contribute to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Dectin-1 is a pathogen recognition receptor in innate immunity. In this study, we investigated the role of Dectin-1 in the pathogenesis of NAFLD. We first showed that Dectin-1 expression was significantly elevated in liver tissues of patients with NASH. NAFLD was induced in mice by feeding high fat diet (HFD) for 24 weeks. At the end of treatment, mice were sacrificed, and their blood and liver tissues were collected for analyses. We showed HFD feeding also increased liver Dectin-1 levels in mice, associated with macrophage infiltration. Either gene knockout or co-administration of a Dectin-1 antagonist laminarin (150 mg/kg twice a day, ip, from 16th week to 24th week) largely protected the livers from HFD-induced lipid accumulation, fibrosis, and elaboration of inflammatory responses. In primary mouse peritoneal macrophages (MPMs), challenge with palmitate (PA, 200 μM), an abundant saturated fatty acid found in NAFLD, significantly activated Dectin-1 signaling pathway, followed by transcriptionally regulated production of pro-inflammatory cytokines. Dectin-1 was required for hepatic macrophage activation and inflammatory factor induction. Condition media generated from Dectin-1 deficient macrophages failed to cause hepatocyte lipid accumulation and hepatic stellate activation. In conclusion, this study provides the primary evidence supporting a deleterious role for Dectin-1 in NAFLD through enhancing macrophage pro-inflammatory responses and suggests that it can be targeted to prevent inflammatory NAFLD.
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Affiliation(s)
- Min-Xiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.,Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China
| | - Lin Ye
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Lei-Ming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Bin Yang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Qian-Hui Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jian-Chang Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Yi Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. .,School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China.
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Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov 2022; 21:799-820. [PMID: 35974096 PMCID: PMC9380983 DOI: 10.1038/s41573-022-00520-5] [Citation(s) in RCA: 963] [Impact Index Per Article: 321.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/11/2022]
Abstract
Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium. Macrophages can promote tumorigenesis and enhance the antitumour response. This Review discusses the molecular mechanisms underlying the reprogramming of macrophages in the tumour microenvironment and provides an overview of macrophage-targeted therapies for the treatment of cancer.
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Affiliation(s)
- Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy. .,IRCCS- Humanitas Research Hospital, Milan, Italy. .,The William Harvey Research Institute, Queen Mary University of London, London, UK.
| | - Paola Allavena
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS- Humanitas Research Hospital, Milan, Italy
| | - Federica Marchesi
- IRCCS- Humanitas Research Hospital, Milan, Italy.,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Cecilia Garlanda
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS- Humanitas Research Hospital, Milan, Italy
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30
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Li H, Qiu D, Yuan Y, Wang X, Wu F, Yang H, Wang S, Ma M, Qian Y, Zhan B, Yang X. Trichinella spiralis cystatin alleviates polymicrobial sepsis through activating regulatory macrophages. Int Immunopharmacol 2022; 109:108907. [PMID: 35691271 DOI: 10.1016/j.intimp.2022.108907] [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] [Received: 03/17/2022] [Revised: 05/19/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Sepsis is a life-threateningorgandysfunction caused by the cytokine storm induced by the severe bacterial infection. Excessive inflammatory responses are responsible for the lethal organ damage during the early stage of sepsis. Helminth infection and helminth-derived proteins have been identified to have the ability to immunomodulate the host immune system by reducing inflammation against inflammatory diseases. Trichinella spiralis cystatin (Ts-Cys) is a cysteine protease inhibitor with strong immunomodulatory functions on host immune system. Our previous studies have shown that excretory-secretory proteins of T. spiralis reduced sepsis-induced inflammation and Ts-Cys was able to inhibit macrophages to produce inflammatory cytokines. Whether Ts-Cys has a therapeutic effect on polymicrobial sepsis and related immunological mechanism are not yet known. METHODS Sepsis was induced in BALB/c mice using cecal ligation and puncture (CLP), followed by intraperitoneal injection of 15 µg recombinant Ts-Cys (rTs-Cys). The therapeutic effect of rTs-Cys on sepsis was evaluated by observing the 72-hour survival rates of CLP-induced septic mice and the acute injury of lung and kidney through measuring the wet/dry weight ratio of lung, the levels of blood urea nitrogen (BUN) and creatinine (Cr) in sera and the tissue section pathology. The potential underlying mechanism was investigated using mouse bone marrow-derived macrophages (BMDMs) by observing the effect of rTs-Cys on LPS-stimulated macrophage polarization. The expression of genes associated with macrophage polarization in BMDMs and tissues of septic mice was measured by Western Blotting and qPCR. RESULTS In this study, we demonstrated the treatment with rTs-Cys alleviated CLP-induced sepsis in mice with significantly reduced pathological injury in vital organs of lung and kidney and reduced mortality of septic mice. The further study identified that treatment with rTs-Cys promoted macrophage polarization from classically activated macrophage (M1) to alternatively activated macrophage (M2) phenotype via inhibiting TLR2/MyD88 signal pathway and increasing expression of mannose receptor (MR), inhibited pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and increased regulatory anti-inflammatory cytokines (IL-10 and TGF-β) in sera and tissues (lung and kidney) of mice with polymicrobial sepsis. CONCLUSIONS Our results demonstrated that rTs-Cys had a therapeutic effect on sepsis through activating regulatory macrophages possibly via suppressing TLR2/MyD88 signal pathway. We also identified that rTs-Cys-induced M2 macrophage differentiation was associated with increased expression of MR on the surface of macrophages. Our results underscored the importance of MR in regulating macrophages during the treatment with rTs-Cys, providing another immunological mechanism in which helminths and their derived proteins modulate the host immune system. The findings in this study suggest that rTs-Cys is a potential therapeutic agent for the prevention and treatment of sepsis and other inflammatory diseases.
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Affiliation(s)
- Huihui Li
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Dapeng Qiu
- Department of Orthopedics, Second Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yuan Yuan
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Xiaoli Wang
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Fengjiao Wu
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Huijuan Yang
- Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shuying Wang
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Mengxi Ma
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Yayun Qian
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China
| | - Bin Zhan
- National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Xiaodi Yang
- Department of Basic Medical College, Bengbu Medical College, Bengbu, China; Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China.
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31
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Heissig B, Salama Y, Tateno M, Takahashi S, Hattori K. siRNA against CD40 delivered via a fungal recognition receptor ameliorates murine acute graft-versus-host disease. EJHAEM 2022; 3:849-861. [PMID: 36051085 PMCID: PMC9421973 DOI: 10.1002/jha2.439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022]
Abstract
Acute graft-versus-host disease (aGvHD) remains a major threat to a successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Although antibody-based targeting of the CD40/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T-cell costimulatory pathway. Here, we used small interfering RNA (siRNA) complexed with β-glucan allowing the binding and uptake of the siRNA/β-glucan complex (siCD40/schizophyllan [SPG]; chemical modifications called NJA-312, NJA-302, and NJA-515) into Dectin1+ cells, which recognize this pathogen-associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40/SPG, NJA-312, and NJA-302 ameliorated aGvHD-mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA-312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA-312 treatment caused delayed initial donor T and B-cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA-312 reduced organ damage by suppressing CCR2+, F4/80+, and IL17A-expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP-recognizing lectin Dectin1 changes the immunological niche, suppresses organ-specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue-specific immune reactions using Pathogen-associated molecular pattern (PAMP) molecules like 1,3-β-glucan for cell delivery of siRNA.
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Affiliation(s)
- Beate Heissig
- Department of Research Support Utilizing Bioresource BankGraduate School of MedicineJuntendo University School of MedicineTokyoJapan
| | - Yousef Salama
- An‐Najah Center for Cancer and Stem Cell ResearchFaculty of Medicine and Health SciencesAn‐Najah National UniversityNablusPalestine
| | - Masatoshi Tateno
- Department of PathologyKushiro Red Cross HospitalKushiroHokkaidoJapan
| | - Satoshi Takahashi
- Division of Clinical Precision Research PlatformInstitute of Medical ScienceUniversity of TokyoTokyoJapan
| | - Koichi Hattori
- Center for Genomic & Regenerative MedicineJuntendo University School of MedicineTokyoJapan
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32
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Li M, Zhang R, Li J, Li J. The Role of C-Type Lectin Receptor Signaling in the Intestinal Microbiota-Inflammation-Cancer Axis. Front Immunol 2022; 13:894445. [PMID: 35619716 PMCID: PMC9127077 DOI: 10.3389/fimmu.2022.894445] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022] Open
Abstract
As a subset of pattern recognition receptors (PRRs), C-type lectin-like receptors (CLRs) are mainly expressed by myeloid cells as both transmembrane and soluble forms. CLRs recognize not only pathogen associated molecular patterns (PAMPs), but also damage-associated molecular patterns (DAMPs) to promote innate immune responses and affect adaptive immune responses. Upon engagement by PAMPs or DAMPs, CLR signaling initiates various biological activities in vivo, such as cytokine secretion and immune cell recruitment. Recently, several CLRs have been implicated as contributory to the pathogenesis of intestinal inflammation, which represents a prominent risk factor for colorectal cancer (CRC). CLRs function as an interface among microbiota, intestinal epithelial barrier and immune system, so we firstly discussed the relationship between dysbiosis caused by microbiota alteration and inflammatory bowel disease (IBD), then focused on the role of CLRs signaling in pathogenesis of IBD (including Mincle, Dectin-3, Dectin-1, DCIR, DC-SIGN, LOX-1 and their downstream CARD9). Given that CLRs mediate intricate inflammatory signals and inflammation plays a significant role in tumorigenesis, we finally highlight the specific effects of CLRs on CRC, especially colitis-associated cancer (CAC), hoping to open new horizons on pathogenesis and therapeutics of IBD and CAC.
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Affiliation(s)
- Muhan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Runfeng Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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33
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Cummings RD. The mannose receptor ligands and the macrophage glycome. Curr Opin Struct Biol 2022; 75:102394. [PMID: 35617912 DOI: 10.1016/j.sbi.2022.102394] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/12/2022] [Accepted: 04/16/2022] [Indexed: 11/03/2022]
Abstract
A unique glycan-binding protein expressed in macrophages and some types of other immune cells is the mannose receptor (MR, CD206). It is an endocytic, transmembrane protein with multiple glycan-binding domains and different specificities in binding glycans. The mannose receptor is important as it has major roles in diverse biological processes, including regulation of circulating levels of reproductive hormones, homeostasis, innate immunity, and infections. These different functions involve the recognition of a wide range of glycans, and their nature is currently under intense study. But the mannose receptor is just one of many glycan-binding proteins expressed in macrophages, leading to an interest in the potential relationship between the macrophage glycome and how it may regulate cognate glycan-binding protein activities. This review focuses primarily on the mannose receptor and its carbohydrate ligands, as well as macrophages and their glycomes.
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Affiliation(s)
- Richard D Cummings
- Beth Israel Deaconess Medical Center, Department of Surgery, Harvard Medical School, CLS 11087 - 3 Blackfan Circle, Boston, MA, 02115, USA.
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34
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Gargani S, Lourou N, Arapatzi C, Tzanos D, Saridaki M, Dushku E, Chatzimike M, Sidiropoulos ND, Andreadou M, Ntafis V, Hatzis P, Kostourou V, Kontoyiannis DL. Inactivation of AUF1 in Myeloid Cells Protects From Allergic Airway and Tumor Infiltration and Impairs the Adenosine-Induced Polarization of Pro-Angiogenic Macrophages. Front Immunol 2022; 13:752215. [PMID: 35222366 PMCID: PMC8873154 DOI: 10.3389/fimmu.2022.752215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
The four isoforms of the RNA-binding protein hnRNPD/AUF1 have been proposed to limit the use of inflammatory mRNAs in innate immune cells. Mice engineered to lack AUF1s in all tissues are sensitive to acute inflammatory assaults; however, they also manifest complex degenerations obscuring assessment of AUF1s’ roles in innate immune cells. Here, we restricted a debilitating AUF1 mutation to the mouse myeloid lineage and performed disease-oriented phenotypic analyses to assess the requirement of AUF1s in variable contexts of innate immune reactivity. Contrary to the whole-body mutants, the myeloid mutants of AUF1s did not show differences in their susceptibility to cytokine storms occurring during endotoxemia; neither in type-I cell-mediated reactions driving intestinal inflammation by chemical irritants. Instead, they were resistant to allergic airway inflammation and displayed reductions in inflammatory infiltrates and an altered T-helper balance. The ex-vivo analysis of macrophages revealed that the loss of AUF1s had a minimal effect on their proinflammatory gene expression. Moreover, AUF1s were dispensable for the classical polarization of cultured macrophages by LPS & IFNγ correlating with the unchanged response of mutant mice to systemic and intestinal inflammation. Notably, AUF1s were also dispensable for the alternative polarization of macrophages by IL4, TGFβ and IL10, known to be engaged in allergic reactions. In contrast, they were required to switch proinflammatory macrophages towards a pro-angiogenic phenotype induced by adenosine receptor signals. Congruent to this, the myeloid mutants of AUF1 displayed lower levels of vascular remodeling factors in exudates from allergen exposed lungs; were unable to support the growth and inflammatory infiltration of transplanted melanoma tumors; and failed to vascularize inert grafts unless supplemented with angiogenic factors. Mechanistically, adenosine receptor signals enhanced the association of AUF1s with the Vegfa, Il12b, and Tnf mRNAs to differentially regulate and facilitate the pro-angiogenic switch. Our data collectively demonstrates that AUF1s do not act as general anti-inflammatory factors in innate immune cells but have more specialized roles in regulons allowing specific innate immune cell transitions to support tissue infiltration and remodeling processes.
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Affiliation(s)
- Sofia Gargani
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Niki Lourou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christina Arapatzi
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Dimitris Tzanos
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Marania Saridaki
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Esmeralda Dushku
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Margarita Chatzimike
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Nikolaos D. Sidiropoulos
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Margarita Andreadou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Vasileios Ntafis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Pantelis Hatzis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Vassiliki Kostourou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Dimitris L. Kontoyiannis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
- *Correspondence: Dimitris L. Kontoyiannis, ;
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35
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Yang W, Zhao P, Li X, Guo L, Gao W. The potential roles of natural plant polysaccharides in inflammatory bowel disease: A review. Carbohydr Polym 2022; 277:118821. [PMID: 34893238 DOI: 10.1016/j.carbpol.2021.118821] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/09/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD) is a long-term chronic disease, about 20% of IBD patients deteriorate to colorectal cancer. Currently, there is no radical cure for IBD. Natural plant polysaccharides (NPP) have low toxic and side effects, which have immune and prebiotic activities and possesses positive effect on alleviating IBD. In this review, we will focus on the alleviating effect of NPP on IBD in vitro and in vivo from three aspects: regulating intestinal flora imbalance, repairing intestinal barrier injury and improving immunity. The relationship between the chemical structure of natural plant polysaccharides and the therapeutic effect of IBD are highlighted. Finally, the synergistic role of NPP as a carrier of drugs or active molecules to reduce side effects and enhance targeting function are discussed, especially pectic polysaccharides. Broadly, this review provides a valuable reference for NPP to be developed as functional food or health products to alleviate IBD.
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Affiliation(s)
- Wenna Yang
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300193, China
| | - Ping Zhao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300193, China
| | - Xia Li
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300193, China.
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300193, China.
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Abstract
Inflammatory bowel diseases (IBD) arise from a convergence of genetic risk, environmental factors, and gut microbiota, where each is necessary but not sufficient to cause disease. Emerging evidence supports a bidirectional relationship between disease progression and changes in microbiota membership and function. Thus, the study of the gut microbiome and host-microbe interactions should provide critical insights into disease pathogenesis as well as leads for developing microbiome-based diagnostics and interventions for IBD. In this article, we review the most recent advances in understanding the relationship between the gut microbiota and IBD and highlight the importance of going beyond establishing description and association to gain mechanistic insights into causes and consequences of IBD. The review aims to contextualize recent findings to form conceptional frameworks for understanding the etiopathogenesis of IBD and for the future development of microbiome-based diagnostics and interventions.
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Affiliation(s)
- Yue Shan
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA;
| | - Mirae Lee
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA; .,Committee on Microbiology, University of Chicago, Chicago, Illinois 60637, USA
| | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA; .,Committee on Microbiology, University of Chicago, Chicago, Illinois 60637, USA
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Rahabi M, Salon M, Bruno-Bonnet C, Prat M, Jacquemin G, Benmoussa K, Alaeddine M, Parny M, Bernad J, Bertrand B, Auffret Y, Robert-Jolimaître P, Alric L, Authier H, Coste A. Bioactive fish collagen peptides weaken intestinal inflammation by orienting colonic macrophages phenotype through mannose receptor activation. Eur J Nutr 2022; 61:2051-2066. [PMID: 34999930 PMCID: PMC9106617 DOI: 10.1007/s00394-021-02787-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 12/14/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE Particular interest is now given to the potential of dietary supplements as alternative non-pharmacological approaches in intestinal inflammation handling. In this aim, this study evaluates the efficiency of fish collagen peptides, Naticol®Gut, on colonic inflammation. METHODS Wild type and Mannose receptor-deficient in the myeloid lineage C57BL/6 mice were administered with Dextran Sodium Sulfate (DSS), Naticol®Gut, DSS, and Naticol®Gut or only water for 4 or 8 days. Inflammatory status was evaluated by establishing macroscopic and microscopic scores, by measuring cytokine and calprotectin production by ELISA and the myeloperoxidase activity by chemiluminescence. Colonic macrophages were phenotyped by measuring mRNA levels of specific markers of inflammation and oxidative status. Colonic immune populations and T-cell activation profiles were determined by flow cytometry. Mucosa-associated gut microbiota assessment was undertaken by qPCR. The phenotype of human blood monocytes from inflammatory bowel disease (IBD) subjects was characterized by RT-qPCR and flow cytometry and their oxidative activity by chemiluminescence. RESULTS Naticol®Gut-treated DSS mice showed attenuated colonic inflammation compared to mice that were only exposed to DSS. Naticol®Gut activity was displayed through its ability to orient the polarization of colonic macrophage towards an anti-inflammatory and anti-oxidant phenotype after its recognition by the mannose receptor. Subsequently, Naticol®Gut delivery modulated CD4 T cells in favor of a Th2 response and dampened CD8 T-cell activation. This immunomodulation resulted in an intestinal eubiosis. In human monocytes from IBD subjects, the treatment with Naticol®Gut also restored an anti-inflammatory and anti-oxidant phenotype. CONCLUSION Naticol®Gut acts as a protective agent against colitis appearing as a new functional food and an innovative and complementary approach in gut health.
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Affiliation(s)
- Mouna Rahabi
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France.,Weishardt International, Rond-Point Georges Jolimaître, BP 259, 81305, Graulhet, France
| | - Marie Salon
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France.,Weishardt International, Rond-Point Georges Jolimaître, BP 259, 81305, Graulhet, France
| | | | - Mélissa Prat
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Godefroy Jacquemin
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Khaddouj Benmoussa
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Mohamad Alaeddine
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Mélissa Parny
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - José Bernad
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Bénédicte Bertrand
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Yannick Auffret
- Weishardt International, Rond-Point Georges Jolimaître, BP 259, 81305, Graulhet, France
| | | | - Laurent Alric
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France.,Department of Internal Medicine and Digestive Diseases, Pôle Digestif, CHU Toulouse, Toulouse, France
| | - Hélène Authier
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Agnès Coste
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France. .,RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France.
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Di J, Gao X, Du Y, Zhang H, Gao J, Zheng A. Size, shape, charge and "stealthy" surface: Carrier properties affect the drug circulation time in vivo. Asian J Pharm Sci 2021; 16:444-458. [PMID: 34703494 PMCID: PMC8520042 DOI: 10.1016/j.ajps.2020.07.005] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/14/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time. For most drugs, sufficient in vivo circulation time is the basis of high bioavailability. Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system, to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect. The physical and chemical properties of drug carriers, such as size, shape, surface charge and surface modification, would affect their in vivo circulation time, metabolic behavior and biodistribution. The final circulation time of carriers is determined by the balance between macrophage recognitions, blood vessel penetration and urine excretion. Therefore, when designing the drug delivery system, we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually. This article mainly reviews the effect of carrier size, size, surface charge and surface properties on its circulation time in vivo, and discusses the mechanism of these properties affecting circulation time. This review has reference significance for the research of long-circulation drug delivery system.
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Affiliation(s)
- Jinwei Di
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xiang Gao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Yimeng Du
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Hui Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Jing Gao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Aiping Zheng
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
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Desamero MJM, Chung SH, Kakuta S. Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models. Int J Mol Sci 2021; 22:4778. [PMID: 33946381 PMCID: PMC8125483 DOI: 10.3390/ijms22094778] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 12/18/2022] Open
Abstract
Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.
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Affiliation(s)
- Mark Joseph Maranan Desamero
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;
- Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna 4031, Philippines
| | - Soo-Hyun Chung
- Division of Experimental Animal Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan;
| | - Shigeru Kakuta
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;
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Rahman S, Davids M, van Hamersveld PHP, Welting O, Rahaoui H, Schuren F, Meijer SL, van den Wijngaard RM, Hakvoort TBM, de Jonge WJ, Heinsbroek SEM. Dietary Curdlan Enhances Bifidobacteria and Reduces Intestinal Inflammation in Mice. Nutrients 2021; 13:1305. [PMID: 33920960 PMCID: PMC8071228 DOI: 10.3390/nu13041305] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
β-glucan consumption is known for its beneficial health effects, but the mode of action is unclear. While humans and mice lack the required enzymes to digest β-glucans, certain intestinal microbes can digest β-glucans, triggering gut microbial changes. Curdlan, a particulate β-glucan isolated from Alcaligenes faecalis, is used as a food additive. In this study we determined the effect of curdlan intake in mice on the intestinal microbiota and dextran sodium sulfate (DSS)-induced intestinal inflammation. The effect of curdlan on the human intestinal microbiota was assessed using i-screen, an assay for studying anaerobic microbial interactions. Mice received oral gavage with vehicle or curdlan for 14 days followed by DSS for 7 days. The curdlan-fed group showed reduced weight loss and colonic inflammation compared to the vehicle-fed group. Curdlan intake did not induce general microbiota community changes, although a specific Bifidobacterium, closely related to Bifidobacterium choerinum, was observed to be 10- to 100-fold more prevalent in the curdlan-fed group under control and colitis conditions, respectively. When tested in i-screen, curdlan induced a global change in the microbial composition of the healthy intestinal microbiota from a human. Overall, these results suggest that dietary curdlan induces microbiota changes that could reduce intestinal inflammation.
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Affiliation(s)
- Shafaque Rahman
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
| | - Mark Davids
- Department of Vascular Medicine, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Patricia H. P. van Hamersveld
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
| | - Olaf Welting
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
| | - Hakim Rahaoui
- The Netherlands Organization for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands; (H.R.); (F.S.)
| | - Frank Schuren
- The Netherlands Organization for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands; (H.R.); (F.S.)
| | - Sybren L. Meijer
- Department of Pathology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - René M. van den Wijngaard
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
| | - Theodorus B. M. Hakvoort
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
- Department of Surgery, University of Bonn, 53113 Bonn, Germany
| | - Sigrid E. M. Heinsbroek
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (S.R.); (P.H.P.v.H.); (O.W.); (R.M.v.d.W.); (T.B.M.H.); (W.J.d.J.)
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Arroyo Portilla C, Tomas J, Gorvel JP, Lelouard H. From Species to Regional and Local Specialization of Intestinal Macrophages. Front Cell Dev Biol 2021; 8:624213. [PMID: 33681185 PMCID: PMC7930007 DOI: 10.3389/fcell.2020.624213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
Initially intended for nutrient uptake, phagocytosis represents a central mechanism of debris removal and host defense against invading pathogens through the entire animal kingdom. In vertebrates and also many invertebrates, macrophages (MFs) and MF-like cells (e.g., coelomocytes and hemocytes) are professional phagocytic cells that seed tissues to maintain homeostasis through pathogen killing, efferocytosis and tissue shaping, repair, and remodeling. Some MF functions are common to all species and tissues, whereas others are specific to their homing tissue. Indeed, shaped by their microenvironment, MFs become adapted to perform particular functions, highlighting their great plasticity and giving rise to high population diversity. Interestingly, the gut displays several anatomic and functional compartments with large pools of strikingly diversified MF populations. This review focuses on recent advances on intestinal MFs in several species, which have allowed to infer their specificity and functions.
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Affiliation(s)
- Cynthia Arroyo Portilla
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.,Departamento de Análisis Clínicos, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
| | - Julie Tomas
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France
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Ma L, Ni L, Yang T, Mao P, Huang X, Luo Y, Jiang Z, Hu L, Zhao Y, Fu Z, Ni Y. Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:1864-1876. [PMID: 33541082 DOI: 10.1021/acs.jafc.0c07095] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Inflammatory bowel disease (IBD) is associated with acute and chronic inflammation of the gastrointestinal tract and has emerged to be a global disease. Spermidine, a natural polyamine, plays a critical role in maintaining cellular homeostasis. Herein, we investigated the impact and mechanism of spermidine on both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis in mice. We found that spermidine exerted protective effects against acute colitis, evidenced by reduced disease activity index (DAI) and colonic inflammation, increased colonic length, and upregulated tight junction proteins in these two colitis models. Importantly, spermidine exerted significant therapeutic and preventive effects against DSS-induced colitis. Pre- and post-treatment with spermidine reduced the expression of proinflammatory cytokines, phosphorylation of (nuclear factor-κB) NF-κB and (mitogen-activated protein kinase) MAPK, and the activation of F4/80 macrophages and T cells in the colon. Furthermore, spermidine upregulated M2 macrophage markers, whereas it downregulated M1 markers in the inflamed colons. In parallel, spermidine reduced M1 pro-inflammatory markers and enhanced M2 anti-inflammatory genes in RAW264.7 cells. These results revealed that spermidine-ameliorated colitis might be through the regulation of M1/M2 macrophage polarization. In addition, spermidine treatment also alleviated LPS/TNF-α-induced inflammation in Caco-2 cells. Taken together, spermidine prevented and reversed colonic inflammation in colitis mice and might be a promising candidate for IBD intervention.
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Affiliation(s)
- Lingyan Ma
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Liyang Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Tianqi Yang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Pei Mao
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Xin Huang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yeqin Luo
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhiyuan Jiang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Luting Hu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yufeng Zhao
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
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Kalia N, Singh J, Kaur M. The role of dectin-1 in health and disease. Immunobiology 2021; 226:152071. [PMID: 33588306 DOI: 10.1016/j.imbio.2021.152071] [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: 08/25/2020] [Revised: 01/07/2021] [Accepted: 01/31/2021] [Indexed: 02/08/2023]
Abstract
Dendritic cell-associated C-type lectin-1 (Dectin-1), also known as β-glucan receptor is an emerging pattern recognition receptor (PRR) which belongs to the family of C-type lectin receptor (CLR). This CLR identifies ligands independently of Ca2+ and is majorly involved in coupling of innate with adaptive immunity. Formerly, Dectin-1 was best known for its role in anti-fungal defense only. However, recent explorations suggested its wider role in defense against variety of infectious diseases caused by pathogens including bacteria, parasites and viruses. In fact, Dectin-1 signaling axis has been suggested to be targeted as an effective therapeutic strategy for cancers. Dectin-1 has also been elucidated ascetically in the heart, respiratory, intestinal, neurological and developmental disorders. Being a defensive PRR, Dectin-1 results in optimal immune responses in collaboration with other PRRs, but the overall evaluation reinforces the hypothesis of disease development on dis-regulation of Dectin-1 activity. This underscores the impact of Dectin-1 polymorphisms in modulating protein expression and generation of non-optimal immune responses through defective collaborations, further underlining their therapeutic potential. To add on, Dectin-1 influence autoimmunity and severe inflammation accredited to recognition of self T cells and apoptotic cells through unknown ligands. Few reports have also testified its redundant role in infections, which makes it a complicated molecule to be fully resolved. Thus, Dectin-1 is a hub that runs a complex collaborative network, whose interactive wire connections to different PRRs are still pending to be revealed. Alternatively, so far focus of almost all the researchers was the two major cell surface isoforms of Dectin-1, despite the fact that its soluble functional intracellular isoform (Dectin-1E) has already been dissected but is indefinable. Therefore, this review intensely recommends the need of future research to resolve the un-resolved and treasure the comprehensive role of Dectin-1 in different clinical outcomes, before determining its therapeutic prospective.
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Affiliation(s)
- Namarta Kalia
- Department of Molecular Biology & Biochemistry, Guru Nanak Dev University, Amritsar 143001, India.
| | - Jatinder Singh
- Department of Molecular Biology & Biochemistry, Guru Nanak Dev University, Amritsar 143001, India
| | - Manpreet Kaur
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143001, India.
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Beheshti-Maal A, Shahrokh S, Ansari S, Mirsamadi ES, Yadegar A, Mirjalali H, Zali MR. Gut mycobiome: The probable determinative role of fungi in IBD patients. Mycoses 2021; 64:468-476. [PMID: 33421192 DOI: 10.1111/myc.13238] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/15/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a multi-factorial autoimmune disorder that its causative agents are unknown. The gut microbiota comprises of bacteria, viruses, fungi and protozoa that its role in IBD has remained controversially. Bacteria constitute more than 99% of the gut microbiota composition, and the main core of the gut microbiota is composed from Bacteroidetes and Firmicutes. The gut microbiota plays an important role in training, development and haemostasis of the immune responses during the life. Fungi compose a very small portion of gut microbiota, but play determinative roles in homeostasis of the gut bacterial composition and the mucosal immune responses. An interkingdom correlation between bacteria and fungi has been suggested. For example, the presence of Salmonella enterica serovar Typhimurium reduces the viability and colonisation of C albicans. Alterations in the composition and function of the gut microbiota, which is known as dysbiosis, are a usual event in patients who suffer from IBD. Although the main reason for this alteration is not clear, the interaction between gut bacteria and gut fungi seems to be an important subject in IBD patients. This review covers new findings on the interaction between fungi and bacteria and the role of fungi in the pathophysiology of IBD.
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Affiliation(s)
- Alireza Beheshti-Maal
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saham Ansari
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elnaz Sadat Mirsamadi
- Department of Microbiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirjalali
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kopiasz Ł, Dziendzikowska K, Gajewska M, Oczkowski M, Majchrzak-Kuligowska K, Królikowski T, Gromadzka-Ostrowska J. Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways-Crohn's Disease Model Study. Nutrients 2021; 13:nu13020321. [PMID: 33499397 PMCID: PMC7911679 DOI: 10.3390/nu13020321] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Crohn’s disease (CD) is characterized by chronic inflammation of the gastrointestinal tract with alternating periods of exacerbation and remission. The aim of this study was to determine the time-dependent effects of dietary oat beta-glucans on colon apoptosis and autophagy in the CD rat model. Methods: A total of 150 Sprague–Dawley rats were divided into two main groups: healthy control (H) and a TNBS (2,4,6-trinitrobenzosulfonic acid)-induced colitis (C) group, both including subgroups fed with feed without beta-glucans (βG−) or feed supplemented with low- (βGl) or high-molar-mass oat beta-glucans (βGh) for 3, 7, or 21 days. The expression of autophagy (LC3B) and apoptosis (Caspase-3) markers, as well as Toll-like (TLRs) and Dectin-1 receptors, in the colon epithelial cells, was determined using immunohistochemistry and Western blot. Results: The results showed that in rats with colitis, after 3 days of induction of inflammation, the expression of Caspase-3 and LC3B in intestinal epithelial cells did not change, while that of TLR 4 and Dectin-1 decreased. Beta-glucan supplementation caused an increase in the expression of TLR 5 and Dectin-1 with no changes in the expression of Caspase-3 and LC3B. After 7 days, a high expression of Caspase-3 was observed in the colitis-induced animals without any changes in the expression of LC3B and TLRs, and simultaneously, a decrease in Dectin-1 expression was observed. The consumption of feed with βGl or βGh resulted in a decrease in Caspase-3 expression and an increase in TLR 5 expression in the CβGl group, with no change in the expression of LC3B and TLR 4. After 21 days, the expression of Caspase-3 and TLRs was not changed by colitis, while that of LC3B and Dectin-1 was decreased. Feed supplementation with βGh resulted in an increase in the expression of both Caspase-3 and LC3B, while the consumption of feed with βGh and βGl increased Dectin-1 expression. However, regardless of the type of nutritional intervention, the expression of TLRs did not change after 21 days. Conclusions: Dietary intake of βGl and βGh significantly reduced colitis by time-dependent modification of autophagy and apoptosis, with βGI exhibiting a stronger effect on apoptosis and βGh on autophagy. The mechanism of this action may be based on the activation of TLRs and Dectin-1 receptor and depends on the period of exacerbation or remission of CD.
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Affiliation(s)
- Łukasz Kopiasz
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland; (Ł.K.); (M.O.); (T.K.); (J.G.-O.)
| | - Katarzyna Dziendzikowska
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland; (Ł.K.); (M.O.); (T.K.); (J.G.-O.)
- Correspondence: ; Tel.: +48-2259-37-033
| | - Małgorzata Gajewska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (M.G.); (K.M.-K.)
| | - Michał Oczkowski
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland; (Ł.K.); (M.O.); (T.K.); (J.G.-O.)
| | - Kinga Majchrzak-Kuligowska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland; (M.G.); (K.M.-K.)
| | - Tomasz Królikowski
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland; (Ł.K.); (M.O.); (T.K.); (J.G.-O.)
| | - Joanna Gromadzka-Ostrowska
- Department of Dietetics, Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland; (Ł.K.); (M.O.); (T.K.); (J.G.-O.)
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H89 Treatment Reduces Intestinal Inflammation and Candida albicans Overgrowth in Mice. Microorganisms 2020; 8:microorganisms8122039. [PMID: 33352792 PMCID: PMC7766101 DOI: 10.3390/microorganisms8122039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/10/2020] [Accepted: 12/17/2020] [Indexed: 12/28/2022] Open
Abstract
Deregulation of the dynamic crosstalk between the gut microbiota, intestinal epithelial cells, and immune cells is critically involved in the development of inflammatory bowel disease and the overgrowth of opportunistic pathogens, including the human opportunistic fungus Candida albicans. In the present study, we assessed the effect of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a protein kinase A inhibitor, on the migration of macrophages to C. albicans through dextran sulphate sodium (DSS)-challenged Caco-2 cells. We also investigated the impact of H89 on intestinal inflammation and C. albicans clearance from the gut, and determined the diversity of the gut microbiota in a murine model of DSS-induced colitis. H89 reduced the migration of macrophages to C. albicans through DSS-challenged Caco-2 cells. In addition, H89 decreased C. albicans viability and diminished the expression of pro-inflammatory cytokines and innate immune receptors in macrophages and colonic epithelial Caco-2 cells. In mice with DSS-induced colitis, H89 attenuated the clinical and histological scores of inflammation and promoted the elimination of C. albicans from the gut. H89 administration to mice decreased the overgrowth of Escherichia coli and Enterococcus faecalis populations while Lactobacillus johnsonii populations increased significantly. Overall, H89 reduced intestinal inflammation and promoted the elimination of C. albicans from the gut.
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