|
1
|
Schulz MC, Wolff N, Kopf M, Gekle M. Acidosis-induced p38-kinase activation triggers an IL-6-mediated crosstalk of renal proximal tubule cells with fibroblasts leading to their inflammatory response. Cell Commun Signal 2025; 23:180. [PMID: 40217316 PMCID: PMC11987431 DOI: 10.1186/s12964-025-02180-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/27/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling. METHODS HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention. RESULTS In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects. CONCLUSION This study identifies IL-6 as a key mediator of tubule-fibroblast crosstalk in an acidic milieu, promoting inflammatory processes. Acidosis induces IL-6 expression, secretion, and biological effects, with p38 kinase as a crucial mediator. If validated in vivo, these findings could enhance understanding of CKD and support early interventions.
Collapse
Affiliation(s)
- Marie-Christin Schulz
- Julius-Bernstein-Institut für Physiologie, Universität Halle- Wittenberg, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
| | - Nathalie Wolff
- Julius-Bernstein-Institut für Physiologie, Universität Halle- Wittenberg, Magdeburger Straße 6, 06112, Halle (Saale), Germany
| | - Michael Kopf
- Julius-Bernstein-Institut für Physiologie, Universität Halle- Wittenberg, Magdeburger Straße 6, 06112, Halle (Saale), Germany
| | - Micheal Gekle
- Julius-Bernstein-Institut für Physiologie, Universität Halle- Wittenberg, Magdeburger Straße 6, 06112, Halle (Saale), Germany
| |
Collapse
|
|
2
|
A L, Qu L, He J, Ge L, Gao H, Huang X, You T, Gong H, Liang Q, Chen S, Xie J, Xu H. Exosomes derived from IFNγ-stimulated mesenchymal stem cells protect photoreceptors in RCS rats by restoring immune homeostasis through tsRNAs. Cell Commun Signal 2024; 22:543. [PMID: 39538308 PMCID: PMC11562488 DOI: 10.1186/s12964-024-01920-3] [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: 07/22/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective of this research was to investigate the mechanisms underlying the safeguarding effects of MSC-derived exosomes in a retinal degenerative disease model. METHODS Interferon gamma-stimulated exosomes (IFNγ-Exos) secreted from MSCs were isolated, purified, and injected into the vitreous body of RCS rats on postnatal day (P) 21. Morphological and functional changes in the retina were examined at P28, P35, P42, and P49 in Royal College of Surgeons (RCS) rats. The mechanism was explored using high-throughput sequencing technology and confirmed in vitro. RESULTS Treatment with IFNγ-Exo produced better protective effects on photoreceptors and improved visual function in RCS rats. IFNγ-Exo significantly suppressed the activated microglia and inhibited the inflammatory responses in the retina of RCS rats, which was also confirmed in the lipopolysaccharide-activated microglia cell line BV2. Furthermore, through tRNA-derived small RNA (tsRNA) sequencing, we found that IFNγ-Exos from MSCs contained higher levels of Other-1_17-tRNA-Phe-GAA-1-M3, Other-6_23-tRNA-Lys-TTT-3, and TRF-57:75-GLN-CGG-2-m2 than native exosomes, which mainly regulated inflammatory and immune-related pathways, including the mTOR signaling pathway and EGFR tyrosine kinase inhibitor resistance. CONCLUSIONS IFNγ stimulation enhanced the neuroprotective effects of MSC-derived exosomes on photoreceptors of the degenerative retina, which may be mediated by immune regulatory tsRNAs acting on microglia. In conclusion, IFNγ-Exo is a promising nanotherapeutic agent for the treatment of retinitis pigmentosa.
Collapse
Affiliation(s)
- Luodan A
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Linghui Qu
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
- Department of Ophthalmology, The 74th Army Group Hospital, Guangzhou, 510318, China
| | - Juncai He
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Lingling Ge
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Hui Gao
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
- Shigatse Branch of Xinqiao Hospital, 953th Hospital, Army Medical University (Third Military Medical University), Shigatse, 857000, China
| | - Xiaona Huang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Tianjing You
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Hong Gong
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
- Department of Military Cognitive Psychology, School of Psychology, Army Medical University, Chongqing, 400038, China
| | - Qingle Liang
- Department of Clinical Laboratory Medicine, First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Siyu Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Jing Xie
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China.
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University, Chongqing, 400038, China.
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
| |
Collapse
|
|
3
|
Fang T, Liu L, Song D, Huang D. The role of MIF in periodontitis: A potential pathogenic driver, biomarker, and therapeutic target. Oral Dis 2024; 30:921-937. [PMID: 36883414 DOI: 10.1111/odi.14558] [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: 01/03/2023] [Revised: 02/08/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023]
Abstract
OBJECTIVE Periodontitis is an inflammatory disease that involves an imbalance in the oral microbiota, activation of inflammatory and immune responses, and alveolar bone destruction. Macrophage migration inhibitory factor (MIF) is a versatile cytokine involved in several pathological reactions, including inflammatory processes and bone destruction, both of which are characteristics of periodontitis. While the roles of MIF in cancer and other immune diseases have been extensively characterized, its role in periodontitis remains inconclusive. RESULTS In this review, we describe a comprehensive analysis of the potential roles of MIF in periodontitis from the perspective of immune response and bone regulation at the cellular and molecular levels. Moreover, we discuss its potential reliability as a novel diagnostic and therapeutic target for periodontitis. CONCLUSION This review can aid dental researchers and clinicians in understanding the current state of MIF-related pathogenesis, diagnosis, and treatment of periodontitis.
Collapse
Affiliation(s)
- Tongfeng Fang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liu Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dongzhe Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dingming Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
4
|
Zhou JX, Cheng AS, Chen L, Li LX, Agborbesong E, Torres VE, Harris PC, Li X. CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease. Cells 2024; 13:489. [PMID: 38534333 PMCID: PMC10968819 DOI: 10.3390/cells13060489] [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: 01/06/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.
Collapse
Affiliation(s)
- Julie Xia Zhou
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Alice Shasha Cheng
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Li Chen
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Linda Xiaoyan Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ewud Agborbesong
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Vicente E. Torres
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Peter C. Harris
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| |
Collapse
|
|
5
|
Christopoulou ME, Skandalis SS, Papakonstantinou E, Stolz D, Aletras AJ. WISP1 induces the expression of macrophage migration inhibitory factor in human lung fibroblasts through Src kinases and EGFR-activated signaling pathways. Am J Physiol Cell Physiol 2024; 326:C850-C865. [PMID: 38145300 PMCID: PMC11193488 DOI: 10.1152/ajpcell.00410.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
Wnt1-inducible signaling protein 1 (WISP1/CCN4) is a secreted matricellular protein that is implicated in lung and airway remodeling. The macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been associated with chronic lung diseases. In this study, we aimed to investigate the WISP1 signaling pathway and its ability to induce the expression of MIF in primary cultures of fibroblasts from normal human lungs (HLFs). Our results showed that WISP1 significantly stimulated the expression of MIF in a concentration- and time-dependent fashion. In WISP1-induced expression of MIF, αvβ5-integrin and chondroitin sulfate proteoglycans as well as Src tyrosine kinases, MAP kinases, phosphatidylinositol 3-kinase/Akt, PKC, and NF-κB were involved. WISP1-induced expression of MIF was attenuated in the presence of the Src kinase inhibitor PP2 or the MIF tautomerase activity inhibitor ISO-1. Moreover, WISP1 significantly increased the phosphorylation and activation of EGF receptor (EGFR) through transactivation by Src kinases. WISP1 also induced the expression of MIF receptor CD74 and coreceptor CD44, through which MIF exerts its effects on HLFs. In addition, it was found that MIF induced its own expression, as well as its receptors CD74/CD44, acting in an autocrine manner. Finally, WISP1-induced MIF promoted the expression of cyclooxygenase 2, prostaglandin E2, IL-6, and matrix metalloproteinase-2 demonstrating the regulatory role of WISP1-MIF axis in lung inflammation and remodeling involving mainly integrin αvβ5, Src kinases, PKC, NF-κB, and EGFR. The specific signaling pathways involved in WISP1-induced expression of MIF may prove to be excellent candidates for novel targets to control inflammation in chronic lung diseases.NEW & NOTEWORTHY The present study demonstrates for the first time that Wnt1-inducible signaling protein 1 (WISP1) regulates migration inhibitory factor (MIF) expression and activity and identifies the main signaling pathways involved. The newly discovered WISP1-MIF axis may drive lung inflammation and could result in the design of novel targeted therapies in inflammatory lung diseases.
Collapse
Affiliation(s)
- Maria-Elpida Christopoulou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Eleni Papakonstantinou
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Daiana Stolz
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Alexios J Aletras
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| |
Collapse
|
|
6
|
Schulz MC, Kopf M, Gekle M. Crosstalk with renal proximal tubule cells drives acidosis-induced inflammatory response and dedifferentiation of fibroblasts via p38-singaling. Cell Commun Signal 2024; 22:148. [PMID: 38395872 PMCID: PMC10893741 DOI: 10.1186/s12964-024-01527-8] [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: 11/13/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Tubulointerstitial kidney disease associated microenvironmental dysregulation, like acidification, inflammation and fibrosis, affects tubule cells and fibroblasts. Micromilieu homeostasis influences intracellular signaling and intercellular crosstalk. Cell-cell communication in turn modulates the interstitial microenvironment. We assessed the impact of acidosis on inflammatory and fibrotic responses in proximal tubule cells and fibroblasts as a function of cellular crosstalk. Furthermore, cellular signaling pathways involved were identified. METHODS HK-2 (human proximal tubule) and CCD-1092Sk (human fibroblasts), in mono and coculture, were exposed to acidic or control media for 3 or 48 h. Protein expression of inflammation markers (TNF, TGF-ß and COX-2), dedifferentiation markers (N-cadherin, vinculin, ß-catenin and vimentin), fibrosis markers (collagen III and fibronectin) and phospho- as well as total MAPK levels were determined by western blot. Secreted collagen III and fibronectin were measured by ELISA. The impact of MAPK activation was assessed by pharmacological intervention. In addition, necrosis, apoptosis and epithelial permeability were determined. RESULTS Independent of culture conditions, acidosis caused a decrease of COX-2, vimentin and fibronectin expression in proximal tubule cells. Only in monoculture, ß-Catenin expression decreased and collagen III expression increased in tubule cells during acidosis. By contrast, in coculture collagen III protein expression of tubule cells was reduced. In fibroblasts acidosis led to an increase of TNF, COX-2, vimentin, vinculin, N-cadherin protein expression and a decrease of TGF-ß expression exclusively in coculture. In monoculture, expression of COX-2 and fibronectin was reduced. Collagen III expression of fibroblasts was reduced by acidosis independent of culture conditions. In coculture, acidosis enhanced phosphorylation of ERK1/2, JNK1/2 and p38 transiently in proximal tubule cells. In fibroblasts, acidosis enhanced phosphorylation of p38 in a sustained and very strong manner. ERK1/2 and JNK1/2 were not affected in fibroblasts. Inhibition of JNK1/2 and p38 under coculture conditions reduced acidosis-induced changes in fibroblasts significantly. CONCLUSIONS Our data show that the crosstalk between proximal tubule cells and fibroblasts is crucial for acidosis-induced dedifferentiation of fibroblasts into an inflammatory phenotype. This dedifferentiation is at least in part mediated by p38 and JNK1/2. Thus, cell-cell communication is essential for the pathophysiological impact of tubulointerstitial acidosis.
Collapse
Affiliation(s)
- Marie-Christin Schulz
- Julius Bernstein Institute of Physiology, Magdeburger Straße 6, 06112, Halle (Saale), Germany.
| | - Michael Kopf
- Julius Bernstein Institute of Physiology, Magdeburger Straße 6, 06112, Halle (Saale), Germany
| | - Michael Gekle
- Julius Bernstein Institute of Physiology, Magdeburger Straße 6, 06112, Halle (Saale), Germany
| |
Collapse
|
|
7
|
Vargas J, Pantouris G. Analysis of CD74 Occurrence in Oncogenic Fusion Proteins. Int J Mol Sci 2023; 24:15981. [PMID: 37958963 PMCID: PMC10650716 DOI: 10.3390/ijms242115981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
CD74 is a type II cell surface receptor found to be highly expressed in several hematological and solid cancers, due to its ability to activate pathways associated with tumor cell survival and proliferation. Over the past 16 years, CD74 has emerged as a commonly detected fusion partner in multiple oncogenic fusion proteins. Studies have found CD74 fusion proteins in a range of cancers, including lung adenocarcinoma, inflammatory breast cancer, and pediatric acute lymphoblastic leukemia. To date, there are five known CD74 fusion proteins, CD74-ROS1, CD74-NTRK1, CD74-NRG1, CD74-NRG2α, and CD74-PDGFRB, with a total of 16 different variants, each with unique genetic signatures. Importantly, the occurrence of CD74 in the formation of fusion proteins has not been well explored despite the fact that ROS1 and NRG1 families utilize CD74 as the primary partner for the formation of oncogenic fusions. Fusion proteins known to be oncogenic drivers, including those of CD74, are typically detected and targeted after standard chemotherapeutic plans fail and the disease relapses. The analysis reported herein provides insights into the early intervention of CD74 fusions and highlights the need for improved routine assessment methods so that targeted therapies can be applied while they are most effective.
Collapse
Affiliation(s)
| | - Georgios Pantouris
- Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA;
| |
Collapse
|
|
8
|
Ruperti F, Becher I, Stokkermans A, Wang L, Marschlich N, Potel C, Maus E, Stein F, Drotleff B, Schippers K, Nickel M, Prevedel R, Musser JM, Savitski MM, Arendt D. Molecular profiling of sponge deflation reveals an ancient relaxant-inflammatory response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.02.551666. [PMID: 37577507 PMCID: PMC10418225 DOI: 10.1101/2023.08.02.551666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
A hallmark of animals is the coordination of whole-body movement. Neurons and muscles are central to this, yet coordinated movements also exist in sponges that lack these cell types. Sponges are sessile animals with a complex canal system for filter-feeding. They undergo whole-body movements resembling "contractions" that lead to canal closure and water expulsion. Here, we combine 3D optical coherence microscopy, pharmacology, and functional proteomics to elucidate anatomy, molecular physiology, and control of these movements. We find them driven by the relaxation of actomyosin stress fibers in epithelial canal cells, which leads to whole-body deflation via collapse of the incurrent and expansion of the excurrent system, controlled by an Akt/NO/PKG/A pathway. A concomitant increase in reactive oxygen species and secretion of proteinases and cytokines indicate an inflammation-like state reminiscent of vascular endothelial cells experiencing oscillatory shear stress. This suggests an ancient relaxant-inflammatory response of perturbed fluid-carrying systems in animals.
Collapse
Affiliation(s)
- Fabian Ruperti
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- Collaboration for joint Ph.D. degree between EMBL and Heidelberg University, Faculty of Biosciences 69117 Heidelberg, Germany
| | - Isabelle Becher
- Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | | | - Ling Wang
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Nick Marschlich
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- Centre for Organismal Studies (COS), University of Heidelberg, 69120 Heidelberg, Germany
| | - Clement Potel
- Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Emanuel Maus
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Frank Stein
- Proteomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Bernhard Drotleff
- Metabolomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Klaske Schippers
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Michael Nickel
- Bionic Consulting Dr. Michael Nickel, 71686 Remseck am Neckar, Germany
| | - Robert Prevedel
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Jacob M Musser
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA
| | - Mikhail M Savitski
- Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- Proteomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Detlev Arendt
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- Centre for Organismal Studies (COS), University of Heidelberg, 69120 Heidelberg, Germany
| |
Collapse
|
|
9
|
Ye S, Mahmood DFD, Ma F, Leng L, Bucala R, Vera PL. Urothelial Oxidative Stress and ERK Activation Mediate HMGB1-Induced Bladder Pain. Cells 2023; 12:1440. [PMID: 37408274 PMCID: PMC10217556 DOI: 10.3390/cells12101440] [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: 04/17/2023] [Revised: 05/08/2023] [Accepted: 05/15/2023] [Indexed: 07/07/2023] Open
Abstract
Activation of intravesical protease activated receptors-4 (PAR4) results in bladder pain through the release of urothelial macrophage migration inhibitory factor (MIF) and high mobility group box-1 (HMGB1). We aimed to identify HMGB1 downstream signaling events at the bladder that mediate HMGB1-induced bladder pain in MIF-deficient mice to exclude any MIF-related effects. We studied whether oxidative stress and ERK activation are involved by examining bladder tissue in mice treated with intravesical disulfide HMGB1 for 1 h and analyzed with Western blot and immunohistochemistry. HMGB1 intravesical treatment increased urothelium 4HNE and phospho-ERK1/2 staining, suggesting that HMGB1 increased urothelial oxidative stress and ERK activation. Furthermore, we examined the functional roles of these events. We evaluated lower abdominal mechanical thresholds (an index of bladder pain) before and 24 h after intravesical PAR4 or disulfide HMGB1. Intravesical pre-treatments (10 min prior) included: N-acetylcysteine amide (NACA, reactive oxygen species scavenger) and FR180204 (FR, selective ERK1/2 inhibitor). Awake micturition parameters (voided volume; frequency) were assessed at 24 h after treatment. Bladders were collected for histology at the end of the experiment. Pre-treatment with NACA or FR significantly prevented HMGB1-induced bladder pain. No significant effects were noted on micturition volume, frequency, inflammation, or edema. Thus, HMGB1 activates downstream urothelial oxidative stress production and ERK1/2 activation to mediate bladder pain. Further dissection of HMGB1 downstream signaling pathway may lead to novel potential therapeutic strategies to treat bladder pain.
Collapse
Affiliation(s)
- Shaojing Ye
- Lexington VA Health Care System, Research & Development, Lexington, KY 40502, USA
| | - Dlovan F. D. Mahmood
- Lexington VA Health Care System, Research & Development, Lexington, KY 40502, USA
| | - Fei Ma
- Lexington VA Health Care System, Research & Development, Lexington, KY 40502, USA
| | - Lin Leng
- Department of Internal Medicine, Yale University, New Haven, CT 06510, USA
| | - Richard Bucala
- Department of Internal Medicine, Yale University, New Haven, CT 06510, USA
| | - Pedro L. Vera
- Lexington VA Health Care System, Research & Development, Lexington, KY 40502, USA
- Department of Physiology, University of Kentucky, Lexington, KY 40506, USA
| |
Collapse
|
|
10
|
Localization of Chicken Rab22a in Cells and Its Relationship to BF or Ii Molecules and Genes. Animals (Basel) 2023; 13:ani13030387. [PMID: 36766276 PMCID: PMC9913282 DOI: 10.3390/ani13030387] [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: 12/03/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Rab22a is an important small GTPase protein the molecule that is involved in intracellular transportation and regulation of proteins. It also plays an important role in antigens uptake, transportation, regulation of endosome morphology, and also regulates the transport of antigens to MHC (Major Histocompatibility Complex) molecules. To investigate the role of Rab22a, the intracellular co-localization of chicken Rab22a (cRab22a) molecule and its relationship to BF and chicken invariant chain (cIi) molecules was studied. A 3D protein structure of Rab22a was constructed by using informatics tools (DNASTAR 4.0 and DNAMAN). Based on the model, the corresponding recombinant eukaryotic plasmids were constructed by point mutations in the protein's structural domains. HEK 293T cells were co-transfected with plasmids pEGFP-C1-cIi to observe the intracellular co-localization. Secondly, the DC2.4 Mouse Dendritic Cell and Murine RAW 264.7 cells were transfected with recombinant plasmids of pmCherry-cRab22a and pmCherry-mRab22a respectively. Subsequently, the intracellular localization of cRab22a in early and late endosomes was observed with specific antibodies against EEA1 and LAMP1 respectively. For gene expression-based studies, the cRab22a gene was down-regulated and up-regulated in HD11 cells, following the detection of transcription levels of the BFa (MHCIa) and cIi genes by real-time quantitative PCR (RT-qPCR). The interactions of the cRab22a gene with BFa and cIi were detected by co-immunoprecipitation (Co-IP) and Western blot. The results showed that the protein structures of chicken and mouse Rab22a were highly homologous (95.4%), and both localize to the early and late endosomes. Ser41 and Tyr74 are key amino acids in the Switch regions of Rab22a which maintain its intracellular localization. The down-regulation of cRab22a gene expression significantly reduced (p < 0.01) the transcription of BFa (MHCIa) and cIi in HD11 cells. However, when the expression of the cRab22a gene was increased 55 times as compared to control cells, the expression of the BFa (MHCIa) gene was increased 1.7 times compared to the control cells (p < 0.01), while the expression of the cIi gene did not significantly differ from control (p > 0.05). Western blot results showed that cRab22a could not directly bind to BFa and cIi. So, cRab22a can regulate BFa and cIi protein molecules indirectly. It is concluded that cRab22a was localized with cIi in the endosome. The Switch regions of cRab22a are the key domains that affect intracellular localization and colocalization of the cIi molecule.
Collapse
|
|
11
|
Astaxanthin ameliorates serum level and spinal expression of macrophage migration inhibitory factor following spinal cord injury. Behav Pharmacol 2022; 33:505-512. [PMID: 36148838 DOI: 10.1097/fbp.0000000000000698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P < 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P < 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.
Collapse
|
|
12
|
Huang S, Qiu Y, Ma Z, Su Z, Hong W, Zuo H, Wu X, Yang Y. A secreted MIF homologue from Trichinella spiralis binds to and interacts with host monocytes. Acta Trop 2022; 234:106615. [PMID: 35901919 DOI: 10.1016/j.actatropica.2022.106615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/17/2022] [Accepted: 07/23/2022] [Indexed: 11/24/2022]
Abstract
Trichinella spiralis is a very successful parasite capable of surviving in many mammal hosts and residing in muscle tissues for long periods, indicating that it must have some effective strategies to escape from or guard against the host immune attack. The functions of MIF have been studied in other parasites and demonstrated to function as a virulence factor aiding in their survival by modulating the host immune response. However, the functions of Trichinella spiralis MIF (TsMIF) have not been addressed. Here, we successfully obtained the purified recombinant TsMIF and anti-TsMIF serum. Our results showed that TsMIF was expressed in all the Trichinella spiralis developmental stages, especially highly expressed in the muscle larvae (ML) and mainly located in stichocytes, midgut, cuticle, muscle cells of ML and around intrauterine embryos of female adults. We also observed TsMIF could be secreted from ML and bind to host monocytes. Next, our data demonstrated that TsMIF not only stimulated the phosphorylation of ERK1/2 and cell proliferation by binding to the host cell surface receptor CD74, but also interacted with a host intracellular protein, Jab1, which is a coactivator of AP-1 transcription. We concluded the secreted TsMIF plays an important role in the interaction between Trichinella spiralis and its host and could be a potential drug or vaccine target molecule against Trichinella spiralis infection.
Collapse
Affiliation(s)
- Shuaiqin Huang
- Department of Parasitology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Yun Qiu
- Department of Biology, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
| | - Zhenrong Ma
- Department of Parasitology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Zhiming Su
- Department of Biology, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
| | - Wenbin Hong
- Department of Biology, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
| | - Heng Zuo
- Department of Biology, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China
| | - Xiang Wu
- Department of Parasitology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - Yurong Yang
- Department of Biology, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
| |
Collapse
|
|
13
|
Varyani F, Löser S, Filbey KJ, Harcus Y, Drurey C, Poveda MC, Rasid O, White MPJ, Smyth DJ, Gerbe F, Jay P, Maizels RM. The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF). Mucosal Immunol 2022; 15:1243-1256. [PMID: 35288645 PMCID: PMC9705247 DOI: 10.1038/s41385-022-00496-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 02/04/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a key innate immune mediator with chemokine- and cytokine-like properties in the inflammatory pathway. While its actions on macrophages are well-studied, its effects on other cell types are less understood. Here we report that MIF is required for expansion of intestinal tuft cells during infection with the helminth Nippostrongylus brasiliensis. MIF-deficient mice show defective innate responses following infection, lacking intestinal epithelial tuft cell hyperplasia or upregulation of goblet cell RELMβ, and fail to expand eosinophil, type 2 innate lymphoid cell (ILC2) and macrophage (M2) populations. Similar effects were observed in MIF-sufficient wild-type mice given the MIF inhibitor 4-IPP. MIF had no direct effect on epithelial cells in organoid cultures, and MIF-deficient intestinal stem cells could generate tuft cells in vitro in the presence of type 2 cytokines. In vivo the lack of MIF could be fully compensated by administration of IL-25, restoring tuft cell differentiation and goblet cell expression of RELM-β, demonstrating its requirement upstream of the ILC2-tuft cell circuit. Both ILC2s and macrophages expressed the MIF receptor CXCR4, indicating that MIF may act as an essential co-factor on both cell types to activate responses to IL-25 in helminth infection.
Collapse
Affiliation(s)
- Fumi Varyani
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
| | - Stephan Löser
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Kara J Filbey
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
- Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Yvonne Harcus
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
| | - Claire Drurey
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Marta Campillo Poveda
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Orhan Rasid
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Madeleine P J White
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Danielle J Smyth
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
- Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK
| | - François Gerbe
- IGF, University of Montpellier, CNRS, Inserm, Montpellier, France
| | - Philippe Jay
- IGF, University of Montpellier, CNRS, Inserm, Montpellier, France
| | - Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| |
Collapse
|
|
14
|
Murtaza S, Tabassum B, Tariq M, Riaz S, Yousaf I, Jabbar B, Khan A, Samuel AO, Zameer M, Nasir IA. Silencing a Myzus persicae Macrophage Inhibitory Factor by Plant-Mediated RNAi Induces Enhanced Aphid Mortality Coupled with Boosted RNAi Efficacy in Transgenic Potato Lines. Mol Biotechnol 2022; 64:1152-1163. [PMID: 35460447 DOI: 10.1007/s12033-022-00498-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/08/2022] [Indexed: 11/28/2022]
Abstract
Myzus persicae causes considerable losses to crops as a major pest. The damage is direct by feeding and also partly indirect because it vectors plant viruses. The currently available control strategies rely on unsafe and nonecofriendly chemical pesticide applications. Plant-mediated RNA interference (RNAi) has emerged as a powerful tool in crop protection from insect pests. Aphid salivary proteins are essential for phloem feeding and act as mediators of the complex interactions between aphids and their host plants. We documented the efficacy of dsRNA directed against macrophage inhibitory factor (MIF1) of M. persicae to induce aphid mortality and gene silencing through the generation of transgenic potato lines. A binary construct harbouring dsMIF1 driven by the CaMV35S promoter was introduced into the local potato variety 'AGB-white' by Agrobacterium-mediated transformation. PCR and Southern blotting validated the transgene presence and genomic integration in seven transgenic potato lines. An in vitro detached leaf assay revealed a significantly high aphid mortality of 65% in the transgenic potato line sDW-2, while the aphid mortality was 77% in the sDW-2 transgenic line during the in planta bioassay in comparison with 19% aphid mortality in the control nontransgenic potato line. A significantly high silencing effect was observed in the mRNA expression of MIF1, which was reduced to 21% in aphids fed on the transgenic potato line sDW-2. However, variable knockdown effects were found among six other transgenic potato lines, ranging from 30 to 62%. The study concluded that plant-mediated silencing of aphid RNA induces significant RNAi in M. persicae, along with enhanced aphid mortality.
Collapse
Affiliation(s)
- Shahid Murtaza
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Bushra Tabassum
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan. .,School of Biological Sciences, University of the Punjab Quaid-I-Azam Campus, Lahore, 54590, Pakistan.
| | - Muhammad Tariq
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Saman Riaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Iqra Yousaf
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Basit Jabbar
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Anwar Khan
- Department of Microbiology, BUITEMS, Quetta, Pakistan
| | | | - Mariam Zameer
- Institute of Molecular Biology & Biotechnology, University of Lahore, Lahore, Pakistan
| | - Idrees Ahmad Nasir
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| |
Collapse
|
|
15
|
Sánchez-Zuno GA, Bucala R, Hernández-Bello J, Román-Fernández IV, García-Chagollán M, Nicoletti F, Matuz-Flores MG, García-Arellano S, Esparza-Michel JA, Cerpa-Cruz S, Pérez-Guerrero EE, Muñoz-Valle JF. Canonical (CD74/CD44) and Non-Canonical (CXCR2, 4 and 7) MIF Receptors Are Differentially Expressed in Rheumatoid Arthritis Patients Evaluated by DAS28-ESR. J Clin Med 2021; 11:jcm11010120. [PMID: 35011861 PMCID: PMC8745239 DOI: 10.3390/jcm11010120] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 02/07/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) significantly contributes to rheumatoid arthritis (RA) pathogenesis. We aimed to evaluate the canonical (CD74/CD44) and non-canonical MIF receptors (CXCR2,4 and 7) expression and sCD74 to establish their association with RA clinical activity according to DAS28-ESR. METHODOLOGY 101 RA patients with different clinical activities (remission (n = 27), low (n = 16), moderate (n = 35) and high (n = 23)) and 9 control subjects (CS) were included. Expression was evaluated by flow cytometry and levels of soluble CD74 (sCD74) by ELISA. Data analysis was performed with FlowJov10.0, STATAv12.0, and GraphPad Prism v7.0. RESULTS According to disease activity, CXCR7 expression (percentage of expression and mean fluorescence intensity (MFI)) was higher in granulocytes from patients in remission, while the expression of CXCR4 was higher in patients with high disease activity (p < 0.05). The expression of CD74 was higher in B cells (p < 0.05) and monocytes (p < 0.01) from patients in remission. Regarding sCD74 levels these were higher in patients with high disease activity when compared to those in remission (p <0.05). CONCLUSIONS The results support the need for further study of the role of sCD74 as a soluble MIF decoy receptor, sequestering it to negatively regulate MIF signaling though its membrane receptors. The expression patterns of CXCR4 and CXCR7 show that the latter is a scavenger-type receptor that prevents endocytosis and even degradation of CXCR4 under inflammatory conditions.
Collapse
Affiliation(s)
- Gabriela Athziri Sánchez-Zuno
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Richard Bucala
- Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA;
| | - Jorge Hernández-Bello
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Ilce Valeria Román-Fernández
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Mariel García-Chagollán
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Mónica Guadalupe Matuz-Flores
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Samuel García-Arellano
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Judith Alejandra Esparza-Michel
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - Sergio Cerpa-Cruz
- Servicio de Reumatología, O.P.D. Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Jalisco 44280, Mexico;
| | - Edsaúl Emilio Pérez-Guerrero
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
| | - José Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco 44340, Mexico; (G.A.S.-Z.); (J.H.-B.); (I.V.R.-F.); (M.G.-C.); (M.G.M.-F.); (S.G.-A.); (J.A.E.-M.); (E.E.P.-G.)
- Correspondence: ; Tel.: +52-(33)-1058-5200 (ext. 33603)
| |
Collapse
|
|
16
|
Abbasi-Habashi S, Jickling GC, Winship IR. Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke. Front Neurol 2021; 12:746486. [PMID: 34956045 PMCID: PMC8695500 DOI: 10.3389/fneur.2021.746486] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.
Collapse
Affiliation(s)
- Sima Abbasi-Habashi
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Glen C Jickling
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Division of Neurology, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Ian R Winship
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
17
|
Hofmann E, Soppert J, Ruhl T, Gousopoulos E, Gerra S, Storti G, Tian Y, Brandhofer M, Schweizer R, Song SY, Lindenblatt N, Pallua N, Bernhagen J, Kim BS. The Role of Macrophage Migration Inhibitory Factor in Adipose-Derived Stem Cells Under Hypoxia. Front Physiol 2021; 12:638448. [PMID: 34366876 PMCID: PMC8334873 DOI: 10.3389/fphys.2021.638448] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 06/21/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue. Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody. Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs. Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.
Collapse
Affiliation(s)
- Elena Hofmann
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany
| | - Josefin Soppert
- Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Institute for Molecular Cardiovascular Research, University Hospital RWTH Aachen, Aachen, Germany.,Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Tim Ruhl
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Epameinondas Gousopoulos
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Simona Gerra
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome "Tor Vergata", Rome, Italy
| | - Yuan Tian
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Markus Brandhofer
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Riccardo Schweizer
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Seung-Yong Song
- Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Nicole Lindenblatt
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Norbert Pallua
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Aesthetic Elite International-Private Clinic, Dusseldorf, Germany
| | - Jürgen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Bong-Sung Kim
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| |
Collapse
|
|
18
|
Ives A, Le Roy D, Théroude C, Bernhagen J, Roger T, Calandra T. Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src/PI3K/myosin II pathway. FASEB J 2021; 35:e21418. [PMID: 33774873 DOI: 10.1096/fj.202001605r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/14/2021] [Accepted: 01/21/2021] [Indexed: 12/18/2022]
Abstract
Constitutively expressed by innate immune cells, the cytokine macrophage migration inhibitory factor (MIF) initiates host immune responses and drives pathogenic responses in infectious, inflammatory, and autoimmune diseases. Dendritic cells (DCs) express high levels of MIF, but the role of MIF in DC function remains poorly characterized. As migration is critical for DC immune surveillance, we investigated whether MIF promoted the migration of DCs. In classical transwell experiments, MIF-/- bone marrow-derived DCs (BMDCs) or MIF+/+ BMDCs treated with ISO-1, an inhibitor of MIF, showed markedly reduced spontaneous migration and chemotaxis. CD74-/- BMDCs that are deficient in the ligand-binding component of the cognate MIF receptor exhibited a migration defect similar to that of MIF-/- BMDCs. Adoptive transfer experiments of LPS-matured MIF+/+ and MIF-/- and of CD74+/+ and CD74-/- BMDCs injected into the hind footpads of homologous or heterologous mice showed that the autocrine and paracrine MIF activity acting via CD74 contributed to the recruitment of DCs to the draining lymph nodes. Mechanistically, MIF activated the Src/PI3K signaling pathway and myosin II complexes, which were required for the migration of BMDCs. Altogether, these data show that the cytokine MIF exerts chemokine-like activity for DC motility and trafficking.
Collapse
Affiliation(s)
- Annette Ives
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Didier Le Roy
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Charlotte Théroude
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thierry Calandra
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| |
Collapse
|
|
19
|
Zhang Y, Liu Z, Wang K, Lu S, Fan S, Xu L, Cai B. Macrophage migration inhibitory factor regulates joint capsule fibrosis by promoting TGF-β1 production in fibroblasts. Int J Biol Sci 2021; 17:1837-1850. [PMID: 33994866 PMCID: PMC8120472 DOI: 10.7150/ijbs.57025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/09/2021] [Indexed: 11/05/2022] Open
Abstract
Joint capsule fibrosis caused by excessive inflammation results in post-traumatic joint contracture (PTJC). Transforming growth factor (TGF)-β1 plays a key role in PTJC by regulating fibroblast functions, however, cytokine-induced TGF-β1 expression in specific cell types remains poorly characterized. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology. In this study, we investigated whether MIF can facilitate TGF-β1 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that MIF and TGF-β1 significantly increased in fibroblasts of injured rat posterior joint capsules. Treatment the lesion sites with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP) reduced TGF-β1 production and relieved joint capsule inflammation and fibrosis. In vitro, MIF facilitated TGF-β1 expression in primary joint capsule fibroblasts by activating mitogen-activated protein kinase (MAPK) (P38, ERK) signaling through coupling with membrane surface receptor CD74, which in turn affected fibroblast functions and promoted MIF production. Our results reveal a novel function of trauma-induced MIF in the occurrence and development of joint capsule fibrosis. Further investigation of the underlying mechanism may provide potential therapeutic targets for PTJC.
Collapse
Affiliation(s)
- Yuxin Zhang
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.,Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Zhonglong Liu
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai 200011, China
| | - Kexin Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Shenji Lu
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Shuai Fan
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Lili Xu
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Bin Cai
- Department of Rehabilitation Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| |
Collapse
|
|
20
|
CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma. Cancer Lett 2021; 508:47-58. [PMID: 33766751 DOI: 10.1016/j.canlet.2021.03.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 01/06/2023]
Abstract
Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC.
Collapse
|
|
21
|
Zhao Y, Ma S, Hu X, Feng M, Xiang R, Li M, Liu C, Lu T, Huang A, Chen J, Wu M, Lu H. JAB1 promotes palmitate-induced insulin resistance via ERK pathway in hepatocytes. J Physiol Biochem 2020; 76:655-662. [PMID: 33051821 DOI: 10.1007/s13105-020-00770-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 10/06/2020] [Indexed: 12/16/2022]
Abstract
Insulin resistance (IR) is the primary pathological mechanism underlying Type 2 diabetes mellitus (T2DM). Many researches have reported the relationship between chronic inflammation and IR, while the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is rapidly activated in inflammatory conditions. However, the functional role of ERK1/2 in IR remains to be identified. We here reported that C-Jun activation domain-binding protein-1 (JAB1) was upregulated in IR. In addition, we showed that depletion of JAB1 led to recovery of insulin sensitivity. Given the fact that JAB1 played as an activator of ERK1/2, we assumed JAB1 was involved in IR through ERK pathway. So we assessed the effects of JAB1 knockdown in palmitate acid (PA) treated HepG2 cells. Importantly, JAB1 siRNA blocked the effect of PA-induced activation of ERK1/2. Furthermore, silencing of JAB1 could reduce the release of inflammatory factors, facilitate hepatic glucose uptake and improve lipid metabolism. All these data implicated that JAB1 knockdown might alleviate PA-induced IR through ERK pathway in hepatocytes.
Collapse
Affiliation(s)
- Yun Zhao
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Suxian Ma
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Xingna Hu
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Min Feng
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Rong Xiang
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Min Li
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Chenxiao Liu
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Ting Lu
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Aijie Huang
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Jiaqi Chen
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Mian Wu
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China
| | - Honghong Lu
- The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People's Republic of China.
| |
Collapse
|
|
22
|
Structural and functional insights into macrophage migration inhibitory factor from Oncomelania hupensis, the intermediate host of Schistosoma japonicum. Biochem J 2020; 477:2133-2151. [PMID: 32484230 DOI: 10.1042/bcj20200068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 11/17/2022]
Abstract
Oncomelania hupensis is the unique intermediate host of Schistosoma japonicum. As an irreplaceable prerequisite in the transmission and prevalence of schistosomiasis japonica, an in-depth study of this obligate host-parasite interaction can provide glimpse into the molecular events in the competition between schistosome infectivity and snail immune resistance. In previous studies, we identified a macrophage migration inhibitory factor (MIF) from O. hupensis (OhMIF), and showed that it was involved in the snail host immune response to the parasite S. japonicum. Here, we determined the crystal structure of OhMIF and revealed that there were distinct structural differences between the mammalian and O. hupensis MIFs. Noticeably, there was a projecting and structured C-terminus in OhMIF, which not only regulated the MIF's thermostability but was also critical in the activation of its tautomerase activity. Comparative studies between OhMIF and human MIF (hMIF) by analyzing the tautomerase activity, oxidoreductase activity, thermostability, interaction with the receptor CD74 and activation of the ERK signaling pathway demonstrated the functional differences between hMIF and OhMIF. Our data shed a species-specific light on structural, functional, and immunological characteristics of OhMIF and enrich the knowledge on the MIF family.
Collapse
|
|
23
|
Lai YC, Chao CH, Yeh TM. Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target. Microorganisms 2020; 8:microorganisms8060891. [PMID: 32545679 PMCID: PMC7356240 DOI: 10.3390/microorganisms8060891] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 12/16/2022] Open
Abstract
Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). Although the cytokine storm has been revealed as a critical factor in dengue disease, the limited understanding of dengue immunopathogenesis hinders the development of effective treatments. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that mediates diverse immune responses, and the serum level of MIF positively correlates with disease severity in patients with dengue. MIF is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. In this paper, the pathogenic roles of MIF and the regulation of MIF secretion during DENV infection are reviewed. Furthermore, whether MIF is a potential therapeutic target against DENV infection is also discussed.
Collapse
Affiliation(s)
- Yen-Chung Lai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (Y.-C.L.); (C.-H.C.)
| | - Chiao-Hsuan Chao
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; (Y.-C.L.); (C.-H.C.)
| | - Trai-Ming Yeh
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Correspondence: ; Tel.: +886-6-2353535 (ext. 5778)
| |
Collapse
|
|
24
|
Wu DM, Zheng ZH, Wang S, Wen X, Han XR, Wang YJ, Shen M, Fan SH, Zhang ZF, Shan Q, Li MQ, Hu B, Zheng YL, Chen GQ, Lu J. Association between plasma macrophage migration inhibitor factor and deep vein thrombosis in patients with spinal cord injuries. Aging (Albany NY) 2020; 11:2447-2456. [PMID: 31036774 PMCID: PMC6520010 DOI: 10.18632/aging.101935] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022]
Abstract
The patients with spinal cord injury (SCI) suffered significantly higher risk of deep vein thrombosis (DVT) than normal population. The aim was to assess the clinical significance of macrophage migration inhibitory factor (MIF) as the risk factor for DVT in acute SCI patients. 207 Chinese patients were enrolled in this study, including thirty-nine (39) patients (18.8 %; 95 %CI: 13.5 %–24.2 %) diagnosed as DVT at the follow-up of 1 month. Nine (9) of the 39 patients (23.1%) were suspected of thrombosis before the screening. The MIF levels in plasma of DVT patients were significantly higher than DVT-free patients. The risks of DVT would be increased by 11 % (OR unadjusted: 1.11; 95% CI, 1.06–1.17, P<0.001) and 8 % (OR adjusted: 1.08; 1.03–1.14, P=0.001), for each additional 1 ng/ml of MIF level. Furthermore, after MIF was combined with established risk factors, area under the receiver operating characteristic curve (standard error) was increased from 0.82(0.035) to 0.85(0.030). The results showed the potential association between the high MIF levels in plasma and elevated DVT risk in SCI patients, which may assist on early intervention.
Collapse
Affiliation(s)
- Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Zi-Hui Zheng
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Shan Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Xin Wen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Xin-Rui Han
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Min Shen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Meng-Qiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| | - Gui-Quan Chen
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, P.R. China
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, P.R. China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, P.R. China
| |
Collapse
|
|
25
|
Illescas O, Pacheco-Fernández T, Laclette JP, Rodriguez T, Rodriguez-Sosa M. Immune modulation by the macrophage migration inhibitory factor (MIF) family: D-dopachrome tautomerase (DDT) is not (always) a backup system. Cytokine 2020; 133:155121. [PMID: 32417648 DOI: 10.1016/j.cyto.2020.155121] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 04/29/2020] [Accepted: 05/06/2020] [Indexed: 01/06/2023]
Abstract
Human macrophage migration inhibition factor (MIF) is a protein with cytokine and chemokine properties that regulates a diverse range of physiological functions related to innate immunity and inflammation. Most research has focused on the role of MIF in different inflammatory diseases. D-dopachrome tautomerase (DDT), a different molecule with structural similarities to MIF, which shares receptors and biological functions, has recently been reported, but little is known about its roles and mechanisms. In this review, we sought to understand the similarities and differences between these molecules by summarizing what is known about their different structures, receptors and mechanisms regulating their expression and biological activities with an emphasis on immunological aspects.
Collapse
Affiliation(s)
- Oscar Illescas
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Thalia Pacheco-Fernández
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Juan P Laclette
- Department of Immunology, Institute of Biomedical Research, Universidad Nacional Autónoma de México (UNAM), Mexico City C.P. 04510, Mexico
| | - Tonathiu Rodriguez
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico
| | - Miriam Rodriguez-Sosa
- Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, MEX C.P. 54090, Mexico.
| |
Collapse
|
|
26
|
Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets? Molecules 2020; 25:molecules25051194. [PMID: 32155795 PMCID: PMC7179464 DOI: 10.3390/molecules25051194] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/17/2022] Open
Abstract
Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.
Collapse
|
|
27
|
Huang Q, Liu H, Zeng J, Li W, Zhang S, Zhang L, Song S, Zhou T, Sutovsky M, Sutovsky P, Pardi R, Hess RA, Zhang Z. COP9 signalosome complex subunit 5, an IFT20 binding partner, is essential to maintain male germ cell survival and acrosome biogenesis†. Biol Reprod 2020; 102:233-247. [PMID: 31373619 PMCID: PMC7443350 DOI: 10.1093/biolre/ioz154] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 06/10/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022] Open
Abstract
Intraflagellar transport protein 20 (IFT20) is essential for spermatogenesis in mice. We discovered that COPS5 was a major binding partner of IFT20. COPS5 is the fifth component of the constitutive photomorphogenic-9 signalosome (COP9), which is involved in protein ubiquitination and degradation. COPS5 is highly abundant in mouse testis. Mice deficiency in COPS5 specifically in male germ cells showed dramatically reduced sperm numbers and were infertile. Testis weight was about one third compared to control adult mice, and germ cells underwent significant apoptosis at a premeiotic stage. Testicular poly (ADP-ribose) polymerase-1, a protein that helps cells to maintain viability, was dramatically decreased, and Caspase-3, a critical executioner of apoptosis, was increased in the mutant mice. Expression level of FANK1, a known COPS5 binding partner, and a key germ cell apoptosis regulator was also reduced. An acrosome marker, lectin PNA, was nearly absent in the few surviving spermatids, and expression level of sperm acrosome associated 1, another acrosomal component was significantly reduced. IFT20 expression level was significantly reduced in the Cops5 knockout mice, and it was no longer present in the acrosome, but remained in the Golgi apparatus of spermatocytes. In the conditional Ift20 mutant mice, COPS5 localization and testicular expression levels were not changed. COP9 has been shown to be involved in multiple signal pathways, particularly functioning as a co-factor for protein ubiquitination. COPS5 is believed to maintain normal spermatogenesis through multiple mechanisms, including maintaining male germ cell survival and acrosome biogenesis, possibly by modulating protein ubiquitination.
Collapse
Affiliation(s)
- Qian Huang
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
| | - Hong Liu
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Zeng
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
| | - Wei Li
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
| | - Shiyang Zhang
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
| | - Ling Zhang
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Shizhen Song
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Ting Zhou
- Department of Occupational and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
| | - Miriam Sutovsky
- Division of Animal Sciences, College of Food, Agriculture and Natural Resources, and Department of Obstetrics, Gynecology and Women’s Health, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Peter Sutovsky
- Division of Animal Sciences, College of Food, Agriculture and Natural Resources, and Department of Obstetrics, Gynecology and Women’s Health, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Ruggero Pardi
- School of Medicine and Scientific Institute, San Raffaele University, Milan, Italy
| | - Rex A Hess
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois, USA
| | - Zhibing Zhang
- Department of Physiology, Wayne State University, Detroit, Michigan, USA
- Department of Obstetrics/Gynecology, Wayne State University, Detroit, Michigan, USA
| |
Collapse
|
|
28
|
Kalotra S, Saini V, Singh H, Sharma A, Kaur G. 5-Nonyloxytryptamine oxalate-embedded collagen-laminin scaffolds augment functional recovery after spinal cord injury in mice. Ann N Y Acad Sci 2019; 1465:99-116. [PMID: 31800108 DOI: 10.1111/nyas.14279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/03/2019] [Accepted: 10/30/2019] [Indexed: 12/22/2022]
Abstract
Polysialic acid (PSA) is crucial for the induction and maintenance of nervous system plasticity and repair after injury. In order to exploit the immense therapeutic potential of PSA, previous studies have focused on the identification and development of peptide-based or synthetic PSA mimetics. 5-Nonyloxytryptamine (5-NOT) has been previously reported as a PSA-mimicking compound for promoting functional recovery after spinal cord injury in mice. In order to explore the neuroregeneration potential of 5-NOT, the current study was based on a biomaterial approach using collagen-laminin (C/L) scaffolds. In in vitro studies, 5-NOT was observed to promote neurite outgrowth, migration, and fasciculation in cerebellar neuronal cells, whereas in 3D cell cultures it showed more ramification and complex Sholl profiles. 5-NOT promoted the survival and neurite length of cortical neurons when cocultured with glutamate-challenged astrocytes. In in vivo studies, spinal cord compression injury mice were used with immediate application of C/L hydrogels impregnated with 5-NOT. C/L + 5-NOT-treated mice demonstrated ∼75% of motor recovery 14 days after injury. Furthermore, this effect was shown to be dependent on the ERK-MAPK pathway and augmentation of cell survival. Thus, based on a biomaterial approach, our current study provides new insight for 5-NOT-containing hydrogels as a promising candidate to speed up recovery after central nervous system injuries.
Collapse
Affiliation(s)
- Shikha Kalotra
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vedangana Saini
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Harpal Singh
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Anuradha Sharma
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Gurcharan Kaur
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India
| |
Collapse
|
|
29
|
Huang H, Chen D, Pu J, Yuan A, Fu Q, Li J, Leng L, Bucala R, Ye S, Lu L. The small molecule macrophage migration inhibitory factor antagonist MIF098, inhibits pulmonary hypertension associated with murine SLE. Int Immunopharmacol 2019; 76:105874. [PMID: 31499270 DOI: 10.1016/j.intimp.2019.105874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/31/2019] [Accepted: 09/01/2019] [Indexed: 01/11/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE), with unclear etiopathogenesis. We evaluated the role of macrophage migration inhibitory factor (MIF), which has been implicated in idiopathic pulmonary hypertension (PH), in SLE-associated PAH. Circulating MIF was measured in SLE patients, SLE-PAH patients, and healthy donors. In situ pulmonary artery MIF protein expression was determined in spontaneous SLE mice (MRL/lpr) and hypoxia-induced C57BL/6J mice. Daily MIF098 was administered to C57BL/6J mice, and these mice were maintained in a hypoxic chamber for 4 weeks. The right ventricular systolic pressure (RVSP) and pathological characteristics of the pulmonary artery (PA), such as hyperproliferation, muscularization, and fibrosis were then measured in each group of mice. Data were also obtained in vitro using pulmonary smooth muscle cells (PASMC) challenged with platelet-derived growth factor (PDGF)-BB or 1% O2 hypoxia. As a result, circulating MIF was elevated in SLE-PAH patients compared with SLE patients or healthy donors. Higher RVSP SLE mice produced more MIF protein than lower RVSP SLE mice in the pulmonary artery. MIF098 decreased RVSP and inhibited distal pulmonary artery hyperproliferation, muscularization, and collagen deposition in hypoxia challenged mice. In addition, MIF098 inhibited PASMC proliferation and migration by regulating mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) signal- and cell-cycle-related proteins. MIF098 also reduced collagen synthesis by inhibiting the TGFβ1/Smad2/Smad3 pathway in cell-based experiments. In conclusion, MIF may serve as a biomarker and a therapeutic target of SLE-associated PAH. Pharmacologic MIF antagonism may be an effective means to ameliorate SLE-PAH.
Collapse
Affiliation(s)
- Huijing Huang
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dandan Chen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jun Pu
- Department of Cardiology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ancai Yuan
- Department of Cardiology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qiong Fu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jia Li
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lin Leng
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Richard Bucala
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Shuang Ye
- Department of Rheumatology, Ren Ji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Liangjing Lu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
30
|
Ssadh HA, Abdulmonem WA, Rasheed Z, Madar IH, Alhoderi J, Eldeen SKN, Alradhwan A, Alasmael N, Alkhamiss A, Fernández N. Knockdown of CD-74 in the Proliferative and Apoptotic Activity of Breast Cancer Cells. Open Access Maced J Med Sci 2019; 7:3169-3176. [PMID: 31949511 PMCID: PMC6953917 DOI: 10.3889/oamjms.2019.354] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/01/2019] [Accepted: 08/02/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The cluster of differentiation (CD) 74 is known for its immunological functions and its elevated level was reported in various cancer cells. AIM The aim of the present study was to investigate the expression and potential roles of CD74 in the proliferative and apoptotic activity of breast cancer. METHODS Expression of CD74, macrophage migration inhibitory factor (MIF) and CD44 was assayed in CAMA-1 and MDA-MB-231 cell lines using flow cytometry. CD74 was knocked down using CD74 siRNA-transfection in CAMA-1, and MDA-MB-231 cells and proliferation and apoptosis were determined in the transfected breast cancer cells. RESULTS The data showed that CD74, MIF and CD44 were expressed in breast cancer cell lines and were associated with cell proliferation and apoptosis. Correlation analysis revealed that CD74 was positively correlated and colocalised with MIF on the cell-surface of CAMA-1 and MDA-MB-231. The knockdown of CD74 significantly reduced CAMA-1 and MDA-MB-231 cell proliferation and increased the level of apoptotic cells. CONCLUSION We concluded that the interactions of CD74 with MIF and CD74 with CD44 could be a potential tumour marker for breast cancer cells. Moreover, the level of co-expression of MIF and CD74 or CD44 could be a surrogate marker for the efficacy of anti-angiogenic drugs, particularly in breast cancer tumours. In short, the study revealed the potential roles of CD74 in the proliferation and apoptosis of breast cancer which may serve as a potential therapeutic target for breast cancer.
Collapse
Affiliation(s)
- Hussain Al Ssadh
- School of Biological Sciences, University of Essex, Colchester, UK
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Qassim, Saudi Arabia
| | - Zafar Rasheed
- Department of Medical Biochemistry, College of Medicine, Qassim University, Saudi Arabia
| | - Inamul Hasan Madar
- Department of Biotechnology and Genetic Engineering, Bharathidasan University, Tiruchirappalli, India
| | - Jamila Alhoderi
- School of Biological Sciences, University of Essex, Colchester, UK
| | - Samah K Nasr Eldeen
- Clinical Laboratory Sciences, Inaya Medical College, Riyadh, Saudi Arabia.,Central Laboratories, Egyptian Ministry of Health, Tanta, Egypt
| | - Ali Alradhwan
- Biochemistry Department, College of Medicine, Imam Abdulrahman Bin Faisal University, Saudi Arabia
| | | | - Abdullah Alkhamiss
- Department of Pathology, College of Medicine, Qassim University, Qassim, Saudi Arabia
| | - Nelson Fernández
- School of Biological Sciences, University of Essex, Colchester, UK
| |
Collapse
|
|
31
|
Hepatocytes derived extracellular vesicles from high-fat diet induced obese mice modulate genes expression and proliferation of islet β cells. Biochem Biophys Res Commun 2019; 516:1159-1166. [DOI: 10.1016/j.bbrc.2019.06.124] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 06/21/2019] [Indexed: 11/24/2022]
|
|
32
|
MIF/CD74 axis participates in inflammatory activation of Schwann cells following sciatic nerve injury. J Mol Histol 2019; 50:355-367. [PMID: 31197516 DOI: 10.1007/s10735-019-09832-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 06/07/2019] [Indexed: 12/17/2022]
Abstract
Based on deep RNA sequencing of distal segments of lesioned sciatic nerves, a huge number of differentially expression genes (DEGs) were thus obtained and functionally analyzed. The inflammatory response was denoted as one of most significant biological processes following sciatic nerve injury. In the present study, ingenuity pathway analysis (IPA) demonstrated that macrophage migration inhibitory factor (MIF) was identified as a core regulator of inflammatory response through interaction with CD74 membrane receptor. By establishment of rat sciatic nerve transection model, we displayed that MIF was upregulated following sciatic nerve axotomy, in colocalization with Schwann cells (SCs). MIF promoted migration, proliferation, together with inflammatory responses of SCs in vitro. Immunoprecipitation showed that MIF interacted with CD74 receptor, through which to activate intracellular ERK and JNK signaling pathways. Interference of CD74 receptor using specific siRNA showed that the transcription of proinflammatory cytokines including TNF-α, IL-1β, as well as cytokine receptor TLR4 in SCs was significantly attenuated, supporting an participation of MIF/CD74 signal axis in SCs inflammatory response. The data provide a novel role of MIF in eliciting inflammatory response of peripheral nerve injury, which might be beneficial for precise therapy of peripheral nerve inflammation.
Collapse
|
|
33
|
Kim J, Kim B, Kim SM, Yang CE, Song SY, Lee WJ, Lee JH. Hypoxia-Induced Epithelial-To-Mesenchymal Transition Mediates Fibroblast Abnormalities via ERK Activation in Cutaneous Wound Healing. Int J Mol Sci 2019; 20:ijms20102546. [PMID: 31137604 PMCID: PMC6566997 DOI: 10.3390/ijms20102546] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 05/17/2019] [Accepted: 05/20/2019] [Indexed: 12/21/2022] Open
Abstract
Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role of ERK in cutaneous scarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associated ERK phosphorylation in abnormal fibroblast activity during cutaneous scarring are unclear. Here, we investigated whether pathologic myofibroblast-like keloid fibroblast activity is promoted by hypoxia-induced epithelial-mesenchymal transition mediated by ERK activation. ERK phosphorylation was significantly increased in keloid tissue and fibroblasts. Human dermal fibroblasts cultured under hypoxia (1% O2) expressed phosphorylated ERK and exhibited activation of p38 mitogen-activated protein kinase signaling. Hypoxic human dermal fibroblasts showed increased protein and mRNA levels of epithelial-mesenchymal transition markers. Furthermore, administration of an ERK inhibitor (SCH772984) reduced the hypoxia-induced elevation of collagen type I levels in human dermal fibroblasts. Therefore, ERK may be a promising therapeutic target in profibrogenic diseases.
Collapse
Affiliation(s)
- Jihee Kim
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
- Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Korea.
| | - Bomi Kim
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Soo Min Kim
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Chae Eun Yang
- Department of Plastic and Reconstructive Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Korea.
| | - Seung Yong Song
- Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Korea.
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Won Jai Lee
- Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Korea.
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Ju Hee Lee
- Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
- Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Korea.
| |
Collapse
|
|
34
|
Ruvolo PP, Hu CW, Qiu Y, Ruvolo VR, Go RL, Hubner SE, Coombes KR, Andreeff M, Qutub AA, Kornblau SM. LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML. EBioMedicine 2019; 44:126-137. [PMID: 31105032 PMCID: PMC6604360 DOI: 10.1016/j.ebiom.2019.05.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/06/2023] Open
Abstract
Background Galectin 3 (LGALS3) gene expression is associated with poor survival in acute myeloid leukemia (AML) but the prognostic impact of LGALS3 protein expression in AML is unknown. LGALS3 supports diverse survival pathways including RAS mediated cascades, protein expression and stability of anti-apoptotic BCL2 family members, and activation of proliferative pathways including those mediated by beta Catenin. CD74 is a positive regulator of CD44 and CXCR4 signaling and this molecule may be critical for AML stem cell function. At present, the role of LGALS3 and CD74 in AML is unclear. In this study, we examine protein expression of LGALS3 and CD74 by reverse phase protein analysis (RPPA) and identify new protein networks associated with these molecules. In addition, we determine prognostic potential of LGALS3, CD74, and their protein networks for clinical correlates in AML patients. Methods RPPA was used to determine relative expression of LGALS3, CD74, and 229 other proteins in 231 fresh AML patient samples and 205 samples were from patients who were treated and evaluable for outcome. Pearson correlation analysis was performed to identify proteins associated with LGALS3 and CD74. Progeny clustering was performed to generate protein networks. String analysis was performed to determine protein:protein interactions in networks and to perform gene ontology analysis. Kaplan-Meir method was used to generate survival curves. Findings LGALS3 is highest in monocytic AML patients and those with elevated LGALS3 had significantly shorter remission duration compared to patients with lower LGALS3 levels (median 21.9 vs 51.3 weeks, p = 0.016). Pearson correlation of LGALS3 with 230 other proteins identifies a distinct set of 37 proteins positively correlated with LGALS3 expression levels with a high representation of proteins involved in AKT and ERK signaling pathways. Thirty-one proteins were negatively correlated with LGALS3 including an AKT phosphatase. Pearson correlation of proteins associated with CD74 identified 12 proteins negatively correlated with CD74 and 16 proteins that are positively correlated with CD74. CD74 network revealed strong association with CD44 signaling and a high representation of apoptosis regulators. Progeny clustering was used to build protein networks based on LGALS3 and CD74 associated proteins. A strong relationship of the LGALS3 network with the CD74 network was identified. For AML patients with both the LGALS3 and CD74 protein cluster active, median overall survival was only 24.3 weeks, median remission duration was 17.8 weeks, and no patient survived beyond one year. Interpretation The findings from this study identify for the first time protein networks associated with LGALS3 and CD74 in AML. Each network features unique pathway characteristics. The data also suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population. Fund Leukemia Lymphoma Society provided funds to SMK for RPPA study of AML patient population. Texas Leukemia provided funds to PPR and SMK to study CD74 and LGALS3 expression in AML patients using RPPA. No payment was involved in the production of this manuscript.
Collapse
Affiliation(s)
- Peter P Ruvolo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Chenyue W Hu
- Department of Biomechanical Engineering, University Texas San Antonio, San Antonio, TX, USA
| | - Yihua Qiu
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivian R Ruvolo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robin L Go
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stefan E Hubner
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kevin R Coombes
- Departments of Biomedical Informatics, The Ohio State University, USA
| | - Michael Andreeff
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amina A Qutub
- Department of Biomechanical Engineering, University Texas San Antonio, San Antonio, TX, USA
| | - Steven M Kornblau
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Molecular Hematology and Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
35
|
Zhang Y, Zhou Y, Chen S, Hu Y, Zhu Z, Wang Y, Du N, Song T, Yang Y, Guo A, Wang Y. Macrophage migration inhibitory factor facilitates prostaglandin E 2 production of astrocytes to tune inflammatory milieu following spinal cord injury. J Neuroinflammation 2019; 16:85. [PMID: 30981278 PMCID: PMC6461812 DOI: 10.1186/s12974-019-1468-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/26/2019] [Indexed: 02/06/2023] Open
Abstract
Background Astrocytes have been shown to produce several pro- and anti-inflammatory cytokines to maintain homeostasis of microenvironment in response to vast array of CNS insults. Some inflammation-related cytokines are responsible for regulating such cell events. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that can be inducibly expressed in the lesioned spinal cord. Unknown is whether MIF can facilitate the production of immunosuppressive factors from astrocytes to tune milieu following spinal cord injury. Methods Following establishment of contusion SCI rat model, correlation of PGE2 synthesis-related protein levels with that of MIF was assayed by Western blot. ELISA assay was used to detect production of PGE2, TNF-α, IL-1β, and IL-6. Immunohistochemistry was performed to observe colocalization of COX2 with GFAP- and S100β-positive astrocytes. The primary astrocytes were treated by various inhibitors to validate relevant signal pathway. Results The protein levels of MIF and COX2, but not of COX1, synchronously increased following spinal cord injury. Treatment of MIF inhibitor 4-IPP to the lesion sites significantly reduced the expression of COX2, mPGES-1, and as a consequence, the production of PGE2. Astrocytes responded robustly to the MIF interference, by which regulated MAPK/COX2/PGE2 signal pathway through coupling with the CD74 membrane receptor. MIF-induced production of PGE2 from astrocytes was able to suppress production of TNF-α, but boosted production of IL-1β and IL-6 in LPS-activated macrophages. Conclusion Collectively, these results reveal a novel function of MIF-mediated astrocytes, which fine-tune inflammatory microenvironment to maintain homeostasis. These suggest an alternative therapeutic strategy for CNS inflammation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1468-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Yuxin Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China.,Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Yue Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China.,Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Shuxia Chen
- Department of Pediatrics, Yancheng City No.1 People's Hospital, Yancheng, 224005, People's Republic of China
| | - Yuming Hu
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Zhenjie Zhu
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Yingjie Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China
| | - Nan Du
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China
| | - Tiancheng Song
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China
| | - Yumin Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China
| | - Aisong Guo
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China.
| | - Yongjun Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China.
| |
Collapse
|
|
36
|
Guo Z, Wang Y, Zhao Y, Shu Y, Liu Z, Zhou H, Wang H, Zhang W. The pivotal oncogenic role of Jab1/CSN5 and its therapeutic implications in human cancer. Gene 2018; 687:219-227. [PMID: 30468907 DOI: 10.1016/j.gene.2018.11.061] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 11/01/2018] [Accepted: 11/19/2018] [Indexed: 01/28/2023]
Abstract
Jab1/CSN5 is a conserved multifunctional protein involved in ubiquitin-mediated protein degradation. Deregulation of Jab1/CSN5 can exert dramatic effects on diverse cellular functions, including DNA repair, cell cycle control, apoptosis, angiogenesis, and signal transduction, all of which are critical for tumor development. Although increasing evidence has demonstrated that Jab1/CSN5 was overexpressed in a variety of human cancers and usually correlated with poor prognosis, little was known about the underlying regulatory principles that coordinated its function. In this review, we highlight recent advances of the oncogenic role of Jab1/CSN5 and its potential as a therapeutic target for anticancer intervention.
Collapse
Affiliation(s)
- Zhen Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Youhong Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Yu Zhao
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China
| | - Hui Wang
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China.
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China.
| |
Collapse
|
|
37
|
Zhou DN, Li SJ, Ding JL, Yin TL, Yang J, Ye H. MIF May Participate in Pathogenesis of Polycystic Ovary Syndrome in Rats through MAPK Signalling Pathway. Curr Med Sci 2018; 38:853-860. [PMID: 30341520 DOI: 10.1007/s11596-018-1953-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 09/04/2018] [Indexed: 12/20/2022]
Abstract
The polycystic ovary syndrome (PCOS) model was established in rats and correlation between the expression of macrophage migration inhibitory factor (MIF) and cytokinesis with the MAPK signalling pathway in the rat ovary was measured. The PCOS model in rats was established by dehydroepiandrosterone (DHEA). Thirty sexually immature female Sprague-Dawley rats were randomly and equally assigned to three groups: control group, PCOS group, and PCOS with high-fat diet (HFD) group. Serum hormones were assayed by radioimmunoassay (RIA). The ovaries were immunohistochemically stained with MIF, and the expression of MIF, p-JNK and p-p38 was detected by Western blotting in ovaries. The serum testosterone level, LH concentration, LH/FSH ratio, fasting insulin level and HOMA IR index in the PCOS group (6.077±0.478, 13.809±1.701, 1.820±0.404, 10.83±1.123 and 1.8692±0.1096) and PCOS with HFD group (6.075±0.439, 14.075±1.927, 1.779±0.277, 10.20±1.377 and 1.7736±0.6851) were significantly higher than those in the control group (4.949±0.337, 2.458±0.509, 1.239±0.038, 9.53±0.548 and 1.5329±0.7363), but there was no significant difference between the PCOS group and PCOS with HFD group. The expression levels of MIF, p-JNK, and p-p38 in the PCOS group (0.4048±0.013, 0.6233±0.093 and 0.7987±0.061) and PCOS with HFD group (0.1929±0.012, 0.3346±0.103 and 0.3468±0.031) were obviously higher than those in control group (0.2492±0.013, 0.3271±0.093 and 0.3393±0.061), but no significant difference was observed between PCOS group and PCOS with HFD group. It was suggested that MIF may participate in the pathogenesis of PCOS through the MAPK signalling pathway in PCOS rats induced by DHEA.
Collapse
Affiliation(s)
- Dan-Ni Zhou
- Chongqing Institute of Reproduction and Genetics, Chongqing Health Center for Women and Children, Chongqing, 400010, China
| | - Sai-Jiao Li
- Reproductive Medical Center, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jin-Li Ding
- Reproductive Medical Center, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Tai-Lang Yin
- Reproductive Medical Center, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jing Yang
- Reproductive Medical Center, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Hong Ye
- Chongqing Institute of Reproduction and Genetics, Chongqing Health Center for Women and Children, Chongqing, 400010, China.
| |
Collapse
|
|
38
|
Liu WT, Lv YJ, Yang RC, Fu JY, Liu L, Wang H, Cao Q, Tan C, Chen HC, Wang XR. New insights into meningitic Escherichia coli infection of brain microvascular endothelial cells from quantitative proteomics analysis. J Neuroinflammation 2018; 15:291. [PMID: 30340642 PMCID: PMC6195690 DOI: 10.1186/s12974-018-1325-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 10/02/2018] [Indexed: 01/08/2023] Open
Abstract
Background Bacterial meningitis remains a big threat to the integrity of the central nervous system (CNS), despite the advancements in antimicrobial reagents. Escherichia coli is a bacterial pathogen that can disrupt the CNS function, especially in neonates. E. coli meningitis occurs after bacteria invade the brain microvascular endothelial cells (BMECs) that form a direct and essential barrier restricting the entry of circulating microbes and toxins to the brain. Previous studies have reported on several cellular proteins that function during meningitic E. coli infections; however, more comprehensive investigations to elucidate the potential targets involved in E. coli meningitis are essential to better understand this disease and discover new treatments for it. Methods The isobaric tags for relative and absolute quantification (iTRAQ) approach coupled with LC-MS/MS were applied to compare and characterize the different proteomic profiles of BMECs in response to meningitic or non-meningitic E. coli strains. KEGG and gene ontology annotations, ingenuity pathways analysis, and functional experiments were combined to identify the key host molecules involved in the meningitic E. coli-induced tight junction breakdown and neuroinflammatory responses. Results A total of 13 cellular proteins were found to be differentially expressed by meningitic E. coli strains PCN033 and RS218, including one that was also affected by HB101, a non-meningitic E. coli strain. Through bioinformatics analysis, we identified the macrophage migration inhibitory factor (MIF), granzyme A, NF-κB signaling, and mitogen-activated protein kinase (MAPK) pathways as being biologically involved in the meningitic E. coli-induced tight junction breakdown and neuroinflammation. Functionally, we showed that MIF facilitated meningitic E. coli-induced production of cytokines and chemokines and also helped to disrupt the blood-brain barrier by decreasing the expression of tight junction proteins like ZO-1, occludin. Moreover, we demonstrated the significant activation of NF-κB and MAPK signaling in BMECs in response to meningitic E. coli strains, which dominantly determined the generation of the proinflammatory cytokines including IL-6, IL-8, TNF-α, and IL-1β. Conclusions Our work identified 12 host cellular targets that are affected by meningitic E. coli strains and revealed MIF to be an important contributor to meningitic E. coli-induced cytokine production and tight junction disruption, and also the NF-κB and MAPK signaling pathways that are mainly involved in the infection-induced cytokines production. Characterization of these distinct proteins and pathways in BMECs will facilitate further elucidation of meningitis-causing mechanisms in humans and animals, thereby enabling the development of novel preventative and therapeutic strategies against infection with meningitic E. coli. Electronic supplementary material The online version of this article (10.1186/s12974-018-1325-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Wen-Tong Liu
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yu-Jin Lv
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.,College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, 450046, Henan, China
| | - Rui-Cheng Yang
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Ji-Yang Fu
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Lu Liu
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Huan Wang
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Qi Cao
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Chen Tan
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.,State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Huan-Chun Chen
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.,State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Xiang-Ru Wang
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, Hubei, China. .,State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
| |
Collapse
|
|
39
|
Zhao S, Molina A, Yu A, Hanson J, Cheung H, Li X, Natkunam Y. High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti-CD74-drug conjugate. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2018; 5:12-24. [PMID: 30191677 PMCID: PMC6317062 DOI: 10.1002/cjp2.114] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/17/2018] [Accepted: 09/04/2018] [Indexed: 12/14/2022]
Abstract
CD74 is a type II transmembrane glycoprotein that functions as an MHC class II chaperone and displays diverse roles in immune responses. Recently, anti‐CD74 immunotherapy has shown promise as an effective treatment strategy for lymphoid neoplasms in preclinical models. Using a human anti‐CD74 antibody (SP7219), we defined the expression of CD74 protein in both normal and over 790 neoplastic hematolymphoid tissue samples. We found that CD74 is expressed broadly in normal B‐cell compartments including primary and secondary lymphoid follicles and in the thymic medulla. The vast majority of lymphomas expressed CD74, including Hodgkin lymphomas (98%), B‐cell lymphomas (96%), extranodal NK/T‐cell lymphomas (88%), mature T‐cell lymphomas (80%), and plasma cell myeloma (75%). Our findings confirm and expand previous observations regarding the expression of CD74 and suggest that CD74 expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and plasma cell malignancies.
Collapse
Affiliation(s)
- Shuchun Zhao
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | | | | | | | | | | | - Yasodha Natkunam
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
40
|
Differential proteomic analysis of actinic keratosis, Bowen’s disease and cutaneous squamous cell carcinoma by label-free LC–MS/MS. J Dermatol Sci 2018; 91:69-78. [PMID: 29665991 DOI: 10.1016/j.jdermsci.2018.04.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 03/06/2018] [Accepted: 04/05/2018] [Indexed: 12/31/2022]
|
|
41
|
Shen D, Lang Y, Chu F, Wu X, Wang Y, Zheng X, Zhang HL, Zhu J, Liu K. Roles of macrophage migration inhibitory factor in Guillain-Barré syndrome and experimental autoimmune neuritis: beneficial or harmful? Expert Opin Ther Targets 2018; 22:567-577. [PMID: 29856236 DOI: 10.1080/14728222.2018.1484109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Macrophage migration inhibitory factor (MIF) plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN), which may offer an opportunity for the development of the novel therapeutic strategies for GBS. Areas covered: 'macrophage migration inhibitory factor' and 'Guillain-Barré syndrome' were used as keywords to search for related publications on Pub-Med, National Center for Biotechnology Information (NCBI), USA. MIF is involved in the etiology of various inflammatory and autoimmune disorders. However, the roles of MIF in GBS and EAN have not been summarized in the publications we identified. Therefore, in this review, we described and analyzed the major roles of MIF in GBS/EAN. Primarily, this molecule aggravates the inflammatory responses in this disorder. However, multiple studies indicated a protective role of MIF in GBS. The potential of MIF as a therapeutic target in GBS has been recently demonstrated in experimental and clinical studies, although clinical trials have been unavailable to date. Expert opinion: MIF plays a critical role in the initiation and progression of GBS and EAN, and it may represent a potential therapeutic target for GBS.
Collapse
Affiliation(s)
- Donghui Shen
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Yue Lang
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Fengna Chu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Xiujuan Wu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Ying Wang
- b Department of Neurobiology, Care Sciences and Society , Division of Neurodegeneration, Karolinska Institute, Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Xiangyu Zheng
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Hong-Liang Zhang
- c Department of Life Sciences , the National Natural Science Foundation of China , Beijing , China
| | - Jie Zhu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China.,b Department of Neurobiology, Care Sciences and Society , Division of Neurodegeneration, Karolinska Institute, Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Kangding Liu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| |
Collapse
|
|
42
|
Macrophage migration inhibitory factor activates inflammatory responses of astrocytes through interaction with CD74 receptor. Oncotarget 2018; 8:2719-2730. [PMID: 27926507 PMCID: PMC5356836 DOI: 10.18632/oncotarget.13739] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 11/22/2016] [Indexed: 01/17/2023] Open
Abstract
Astrocytes, the major glial cell population of the central nervous system (CNS), play important physiological roles related to CNS homeostasis. Growing evidence demonstrates that astrocytes trigger innate immune responses under challenge of a variety of proinflammatory cytokines. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine mainly secreted from monocytes/macrophages, is involved in inflammation-associated pathophysiology. Here, we displayed that expression of MIF significantly increased following spinal cord injury, in colocalization with microglia and astrocytes. MIF elicited inflammatory responses of astrocytes via activation of CD74 receptor and extracellular signal-related kinase (ERK) pathway. Transcriptome analysis revealed that inflammation-related factors cholesterol 25-hydroxylase (Ch25h) and phospholipase A2-IIA (Pla2g2a), downstream of MIF/CD74 axis, were potentially implicated in the mediating inflammatory response of astrocytes. Our results provided a new target for interference of CNS inflammation after insults.
Collapse
|
|
43
|
Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer. Oncotarget 2018; 7:73486-73496. [PMID: 27636991 PMCID: PMC5341993 DOI: 10.18632/oncotarget.11970] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 09/02/2016] [Indexed: 01/16/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases. In this article, we report that oxMIF is also linked to different solid tumors as it is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian and lung cancer. Furthermore, oxMIF can be specifically targeted by a subset of phage display-derived fully human, monoclonal anti-MIF antibodies (mAbs) that were shown to neutralize pro-tumorigenic activities of MIF in vivo. We further demonstrate that anti-oxMIF mAbs sensitize human cancer cell lines (LNCaP, PC3, A2780 and A2780ADR) to the action of cytotoxic drugs (mitoxantrone, cisplatin and doxorubicin) in vitro and in an A2780 xenograft mouse model of ovarian cancer. We conclude that oxMIF is the disease related isoform of MIF in solid tumors and a potential new diagnostic marker and drug target in cancer.
Collapse
|
|
44
|
Barald KF, Shen YC, Bianchi LM. Chemokines and cytokines on the neuroimmunoaxis: Inner ear neurotrophic cytokines in development and disease. Prospects for repair? Exp Neurol 2018; 301:92-99. [DOI: 10.1016/j.expneurol.2017.10.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 09/18/2017] [Accepted: 10/12/2017] [Indexed: 01/22/2023]
|
|
45
|
Huang S, Pengsakul T, Cao Y, Lu M, Peng W, Lin J, Tang C, Tang L. Biological activities and functional analysis of macrophage migration inhibitory factor in Oncomelania hupensis, the intermediate host of Schistosoma japonicum. FISH & SHELLFISH IMMUNOLOGY 2018; 74:133-140. [PMID: 29305986 DOI: 10.1016/j.fsi.2017.12.065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 12/26/2017] [Accepted: 12/31/2017] [Indexed: 06/07/2023]
Abstract
Schistosomiasis is a destructive parasitic zoonosis caused by agents of the genus Schistosoma, which afflicts more than 250 million people worldwide. The freshwater amphibious snail Oncomelania hupensis serves as the obligate intermediate host of Schistosoma japonicum. Macrophage migration inhibitory factor (MIF) has been demonstrated to be a pleiotropic immunoregulatory cytokine and a key signaling molecule involved in adaptive and innate immunity. In the present study, we obtained the full-length cDNA of OhMIF and analyzed the characteristics of the ORF and the peptide sequence in O. hupensis. Next we have successfully expressed and purified the recombinant OhMIF protein (rOhMIF) together with a site-directed mutant rOhMIFP2G, in which the N-terminal Proline (Pro2) was substituted by a Gly. Our results indicated that rOhMIF displayed the conserved D-dopachrome tautomerase activity which is dependent on Pro2, and this enzymatic activity can be significantly inhibited by the MIF antagonist ISO-1. Moreover, we also measured and compared the steady state kinetic values for D-dopachrome tautomerase activity of rOhMIF and rHsMIF, and the results showed that the reaction rate, catalytic efficiency and substrate affinity of rOhMIF are significantly lower than those of rHsMIF. Additionally, we also showed that rOhMIF had the oxidoreductase activity which can utilize DTT as reductant to reduce insulin. Furthermore, the results obtained from the in vitro injection assay demonstrated that rOhMIF and its mutant rOhMIFP2G can also induce the phosphorylation and activation of ERK1/2 pathway in O. hupensis circulating hemocytes, indicating that the tautomerase activity is not required for this biological function. These results are expected to produce a better understanding of the internal immune defense system in O. hupensis, and help to further explore the interaction between O. hupensis and its natural parasite S. japoniucm.
Collapse
Affiliation(s)
- Shuaiqin Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
| | - Theerakamol Pengsakul
- Faculty of Medical Technology, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Yunchao Cao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Mingke Lu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Wenfeng Peng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiaojiao Lin
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Key Laboratory of Animal Parasitology, Ministry of Agriculture of China, Shanghai, China
| | - Chongti Tang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Liang Tang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China; Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
| |
Collapse
|
|
46
|
MIF Inhibitor ISO-1 Protects Photoreceptors and Reduces Gliosis in Experimental Retinal Detachment. Sci Rep 2017; 7:14336. [PMID: 29084983 PMCID: PMC5662618 DOI: 10.1038/s41598-017-14298-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/06/2017] [Indexed: 01/16/2023] Open
Abstract
Photoreceptor death and retinal gliosis underlie the majority of vision threatening retinal diseases including retinal detachment (RD). Although the underlying pathobiology of vision limiting processes in RD is not fully understood, inflammation is known to play a critical role. We conducted an iTRAQ proteomic screen of up- and down-regulated proteins in a murine model of RD to identify potential targetable candidates. Macrophage migration inhibitory factor (MIF) was identified and evaluated for neurotoxic and pro-gliotic effects during RD. Systemic administration of the MIF inhibitor ISO-1 significantly blocked photoreceptor apoptosis, outer nuclear layer (ONL) thinning, and retinal gliosis. ISO-1 and MIF knockout (MIFKO) had greater accumulation of Müller glia pERK expression in the detached retina, suggesting that Müller survival pathways might underlie the neuroprotective response. Our data show the feasibility of the MIF-inhibitor ISO-1 to block pathological damage responses in retinal detachment and provide a rationale to explore MIF inhibition as a potential therapeutic option for RD.
Collapse
|
|
47
|
Lechien JR, Nassri A, Kindt N, Brown DN, Journe F, Saussez S. Role of macrophage migration inhibitory factor in head and neck cancer and novel therapeutic targets: A systematic review. Head Neck 2017; 39:2573-2584. [PMID: 28963807 DOI: 10.1002/hed.24939] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 06/22/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in systemic, autoimmune, and inflammatory diseases, such as obesity, rheumatoid arthritis, and systemic lupus erythematosus. For the 2 past decades, MIF has been reported to participate in carcinogenesis, disease prognosis, tumor cell proliferation, invasion, and tumor-induced angiogenesis in many cancers. The purpose of this article is to review published experimental and clinical data for MIF and its involvement in upper aerodigestive tract cancers. Based on the current literature, we propose a biomolecular model describing the mechanisms underlying the involvement of MIF in the initiation, progression, apoptosis, and proliferation of head and neck tumor cells. In reference to this model, potential therapeutic approaches based on the use of MIF antagonists and neutralizing antibodies are described. It is concluded that MIF is a promising target for future therapeutic strategies, both with and without chemoradiation strategies.
Collapse
Affiliation(s)
- Jérôme R Lechien
- Department of Otolaryngology and Head and Neck Surgery, RHMS Baudour, EpiCURA Hospital, Baudour, Belgium.,Laboratory of Phonetics, Faculty of Psychology, Research Institute for Language sciences and Technology, University of Mons (UMONS), Mons, Belgium.,Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Amir Nassri
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Nadege Kindt
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - David N Brown
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Fabrice Journe
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium.,Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Sven Saussez
- Department of Otolaryngology and Head and Neck Surgery, RHMS Baudour, EpiCURA Hospital, Baudour, Belgium.,Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| |
Collapse
|
|
48
|
Weber LJ, Marcy HK, Shen YC, Tomkovich SE, Brooks KM, Hilk KE, Barald KF. The role of jab1, a putative downstream effector of the neurotrophic cytokine macrophage migration inhibitory factor (MIF) in zebrafish inner ear hair cell development. Exp Neurol 2017; 301:100-109. [PMID: 28928022 DOI: 10.1016/j.expneurol.2017.09.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 09/05/2017] [Accepted: 09/12/2017] [Indexed: 01/12/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a neurotrophic cytokine essential for inner ear hair cell (HC) development and statoacoustic ganglion (SAG) neurite outgrowth, and SAG survival in mouse, chick and zebrafish. Another neurotrophic cytokine, Monocyte chemoattractant protein 1 (MCP1) is known to synergize with MIF; but MCP1 alone is insufficient to support mouse/chick SAG neurite outgrowth or neuronal survival. Because of the relatively short time over which the zebrafish inner ear develops (~30hpf), the living zebrafish embryo is an ideal system to examine mif and mcp1 cytokine pathways and interactions. We used a novel technique: direct delivery of antisense oligonucleotide morpholinos (MOs) into the embryonic zebrafish otocyst to discover downstream effectors of mif as well as to clarify the relationship between mif and mcp1 in inner ear development. MOs for mif, mcp1 and the presumptive mif and mcp1 effector, c-Jun activation domain-binding protein-1 (jab1), were injected and then electroporated into the zebrafish otocyst 25-48hours post fertilization (hpf). We found that although mif is important at early stages (before 30hpf) for auditory macular HC development, jab1 is more critical for vestibular macular HC development before 30hpf. After 30hpf, mcp1 becomes important for HC development in both maculae.
Collapse
Affiliation(s)
- Loren J Weber
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
| | - Hannah K Marcy
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Undergraduate Research Opportunity Program, 1190 Undergraduate Science Building, 204 Washtenaw Avenue, Ann Arbor, MI 48109-2215, USA.
| | - Yu-Chi Shen
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
| | - Sarah E Tomkovich
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Undergraduate Research Opportunity Program, 1190 Undergraduate Science Building, 204 Washtenaw Avenue, Ann Arbor, MI 48109-2215, USA.
| | - Kristina M Brooks
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
| | - Kelly E Hilk
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Undergraduate Research Opportunity Program, 1190 Undergraduate Science Building, 204 Washtenaw Avenue, Ann Arbor, MI 48109-2215, USA.
| | - Kate F Barald
- Department of Cell and Developmental Biology, University of Michigan Medical School, 3728 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-0619, USA; Department of Biomedical Engineering, College of Engineering, 2200 Bonisteel Boulevard, University of Michigan, Ann Arbor, MI 48109-2099, USA.
| |
Collapse
|
|
49
|
Identification and functional characterization of Oncomelania hupensis macrophage migration inhibitory factor involved in the snail host innate immune response to the parasite Schistosoma japonicum. Int J Parasitol 2017; 47:485-499. [DOI: 10.1016/j.ijpara.2017.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/17/2017] [Accepted: 01/18/2017] [Indexed: 01/09/2023]
|
|
50
|
Tilstam PV, Qi D, Leng L, Young L, Bucala R. MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics. Expert Opin Ther Targets 2017; 21:671-683. [PMID: 28562118 DOI: 10.1080/14728222.2017.1336227] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.
Collapse
Affiliation(s)
- Pathricia V Tilstam
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Dake Qi
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA.,b Department of Biomedical Sciences , Memorial University of Newfoundland , St. John's , Canada
| | - Lin Leng
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Lawrence Young
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| | - Richard Bucala
- a Department of Internal Medicine , Yale University School of Medicine , New Haven , CT , USA
| |
Collapse
|