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Chen Z, Zhao Q, Chen L, Gao S, Meng L, Liu Y, Wang Y, Li T, Xue J. MAGP2 promotes osteogenic differentiation during fracture healing through its crosstalk with the β-catenin pathway. J Cell Physiol 2024; 239:e31183. [PMID: 38348695 DOI: 10.1002/jcp.31183] [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: 10/12/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 04/12/2024]
Abstract
Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating β-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and β-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, β-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with β-catenin/TCF4 to enhance β-catenin/TCF4's function and activate LRP5-activated β-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.
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Affiliation(s)
- Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qi Zhao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lianghong Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Songlan Gao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lingshuai Meng
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yingjie Liu
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tiegang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Meloxicam Inhibits Apoptosis in Neurons by Deactivating Tumor Necrosis Factor Receptor Superfamily Member 25, Leading to the Decreased Cleavage of DNA Fragmentation Factor Subunit α in Alzheimer's Disease. Mol Neurobiol 2023; 60:395-412. [PMID: 36279100 DOI: 10.1007/s12035-022-03091-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/10/2022] [Indexed: 12/30/2022]
Abstract
Neuronal apoptosis is considered to be a critical cause of Alzheimer's disease (AD). Recently, meloxicam has shown neuroprotective effects; however, the inherent mechanisms are highly overlooked. Using APP/PS1 transgenic (Tg) mice as in vivo animal models, we found that meloxicam inhibits apoptosis in neurons by deactivating tumor necrosis factor receptor superfamily member 25 (TNFRSF25), leading to the suppression of the expression of fas-associated protein with death domain (FADD) and the cleavage of DNA fragmentation factor subunit α (DFFA) and cysteine aspartic acid protease-3 (caspase 3) via β-amyloid protein (Aβ)-depressing mechanisms. Moreover, the meloxicam treatment blocked the effects of β-amyloid protein oligomers (Aβo) on stimulating the synthesis of tumor necrosis factor α (TNF-α) and TNF-like ligand 1A (TL1A) in neuroblastoma (N) 2a cells. TNF-α and TL1A induce apoptosis in neurons via TNFR- and TNFRSF25-dependent caspase 3-activating mechanisms, respectively. Knocking down the expression of TNFRSF25 blocked the effects of TL1A on inducing apoptosis in neurons by deactivating the signaling cascades of FADD, caspase 3, and DFFA. Consistently, TNFRSF25 shRNA blocked the effects of Aβo on inducing neuronal apoptosis, which was corroborated by the efficacy of meloxicam in inhibiting Aβo-induced neuronal apoptosis. By ameliorating neuronal apoptosis, meloxicam improved memory loss in APP/PS1 Tg mice.
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Zheng L, Adam SA, García‐Anoveros J, Mitchell BJ, Bartles JR. Espin overexpression causes stereocilia defects and provides an anti-capping effect on actin polymerization. Cytoskeleton (Hoboken) 2022; 79:64-74. [PMID: 35844198 PMCID: PMC9796729 DOI: 10.1002/cm.21719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/01/2022] [Accepted: 07/12/2022] [Indexed: 01/30/2023]
Abstract
Stereocilia are actin-based projections of hair cells that are arranged in a step like array, in rows of increasing height, and that constitute the mechanosensory organelle used for the senses of hearing and balance. In order to function properly, stereocilia must attain precise sizes in different hair cell types and must coordinately form distinct rows with varying lengths. Espins are actin-bundling proteins that have a well-characterized role in stereocilia formation; loss of function mutations in Espin result in shorter stereocilia and deafness in the jerker mouse. Here we describe the generation of an Espin overexpressing transgenic mouse line that results in longer first row stereocilia and discoordination of second-row stereocilia length. Furthermore, Espin overexpression results in the misregulation of other stereocilia factors including GNAI3, GPSM2, EPS8, WHRN, and MYO15A, revealing that GNAI3 and GPSM2 are dispensable for stereocilia overgrowth. Finally, using an in vitro actin polymerization assay we show that espin provides an anti-capping function that requires both the G-actin binding WH2 domain as well as either the C-terminal F-actin binding domain or the internal xAB actin-binding domain. Our results provide a novel function for Espins at the barbed ends of actin filaments distinct from its previous known function of actin bundling that may account for their effects on stereocilia growth.
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Affiliation(s)
- Lili Zheng
- Department of Cell and Developmental BiologyNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA
| | - Stephen A. Adam
- Department of Cell and Developmental BiologyNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA
| | - Jaime García‐Anoveros
- Department of Anesthesiology Neurology and NeuroscienceNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA,Hugh Knowles Center for Clinical and Basic Science in Hearing and its DisordersNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA
| | - Brian J. Mitchell
- Department of Cell and Developmental BiologyNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA
| | - James R. Bartles
- Department of Cell and Developmental BiologyNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA,Hugh Knowles Center for Clinical and Basic Science in Hearing and its DisordersNorthwestern University, Feinberg School of MedicineChicagoIllinoisUSA
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Collins FL, Stone MD, Turton J, McCabe LR, Wang ECY, Williams AS. Oestrogen-deficiency induces bone loss by modulating CD14 + monocyte and CD4 + T cell DR3 expression and serum TL1A levels. BMC Musculoskelet Disord 2019; 20:326. [PMID: 31299941 PMCID: PMC6626337 DOI: 10.1186/s12891-019-2704-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 07/03/2019] [Indexed: 12/13/2022] Open
Abstract
Background Oestrogen-deficiency induced by menopause is associated with reduced bone density and primary osteoporosis, resulting in an increased risk of fracture. While the exact etiology of menopause-induced primary osteoporotic bone loss is not fully known, members of the tumour necrosis factor super family (TNFSF) are known to play a role. Recent studies have revealed that the TNFSF members death receptor 3 (DR3) and one of its ligands, TNF-like protein 1A (TL1A) have a key role in secondary osteoporosis; enhancing CD14+ peripheral blood mononuclear cell (PBMC) osteoclast formation and bone resorption. Whether DR3 and TL1A contribute towards bone loss in menopause-induced primary osteoporosis however, remains unknown. Methods To investigate this we performed flow cytometry analysis of DR3 expression on CD14+ PBMCs isolated from pre- and early post-menopausal females and late post-menopausal osteoporotic patients. Serum levels of TL1A, CCL3 and total MMP-9 were measured by ELISA. In vitro osteoclast differentiation assays were performed to determine CD14+ monocyte osteoclastogenic potential. In addition, splenic CD4+ T cell DR3 expression was investigated 1 week and 8 weeks post-surgery, using the murine ovariectomy model. Results In contrast to pre-menopausal females, CD14+ monocytes isolated from post-menopausal females were unable to induce DR3 expression. Serum TL1A levels were decreased approx. 2-fold in early post-menopausal females compared to pre-menopausal controls and post-menopausal osteoporotic females; no difference was observed between pre-menopausal and late post-menopausal osteoporotic females. Analysis of in vitro CD14+ monocyte osteoclastogenic potential revealed no significant difference between the post-menopausal and post-menopausal osteoporotic cohorts. Interestingly, in the murine ovariectomy model splenic CD4+ T cell DR3 expression was significantly increased at 1 week but not 8 weeks post-surgery when compared to the sham control. Conclusion Our results reveals for the first time that loss of oestrogen has a significant effect on DR3; decreasing expression on CD14+ monocytes and increasing expression on CD4+ T cells. These data suggest that while oestrogen-deficiency induced changes in DR3 expression do not affect late post-menopausal bone loss they could potentially have an indirect role in early menopausal bone loss through the modulation of T cell activity.
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Affiliation(s)
- Fraser L Collins
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. .,Department of Physiology, Michigan State University, East Lansing, MI, USA.
| | - Michael D Stone
- University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff, UK
| | - Jane Turton
- University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff, UK
| | - Laura R McCabe
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Eddie C Y Wang
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Anwen S Williams
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
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Williams A, Wang ECY, Thurner L, Liu CJ. Review: Novel Insights Into Tumor Necrosis Factor Receptor, Death Receptor 3, and Progranulin Pathways in Arthritis and Bone Remodeling. Arthritis Rheumatol 2018; 68:2845-2856. [PMID: 27428882 PMCID: PMC5599977 DOI: 10.1002/art.39816] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 07/12/2016] [Indexed: 12/27/2022]
Affiliation(s)
| | | | - Lorenz Thurner
- Saarland University Medical School, Homburg, Saar, Germany
| | - Chuan-Ju Liu
- New York University Medical Center, New York, New York
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Singh RK, Perks WV, Twohig JP, Kidd EJ, Broadley K, Farrow SN, Williams AS, Taylor PR, Wang ECY. Death Receptor 3 regulates distinct pathological attributes of acute versus chronic murine allergic lung inflammation. Cell Immunol 2017; 320:62-70. [PMID: 28942944 PMCID: PMC5736020 DOI: 10.1016/j.cellimm.2017.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 09/08/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022]
Abstract
The Death Receptor 3 (DR3)/Tumour Necrosis Factor-like cytokine 1A (TL1A) axis stimulates effector T cells and type 2 innate lymphocytes (ILC2) that trigger cytokine release and drive disease pathology in several inflammatory and autoimmune diseases, including murine models of acute allergic lung inflammation (ALI). The aim of this study was to elucidate the role of DR3 in chronic ALI compared to acute ALI, using mice genetically deficient in the DR3 gene (DR3ko). Results showed DR3 expression in the lungs of wild-type mice was up-regulated following induction of acute ALI and this increased expression was maintained in chronic disease. DR3ko mice were resistant to cellular accumulation within the alveolar passages in acute, but not chronic ALI. However, DR3ko mice displayed reduced immuno-histopathology and goblet cell hyperplasia; hallmarks of the asthmatic phenotype; in chronic, but not acute ALI. These data suggest DR3 is a potential therapeutic target, involved in temporally distinct aspects of ALI progression and pathogenesis.
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Affiliation(s)
- Ravinder Kaur Singh
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - William Victor Perks
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Jason Peter Twohig
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Emma J Kidd
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK
| | - Kenneth Broadley
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK
| | - Stuart N Farrow
- CRT discoveries laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK
| | - Anwen Sian Williams
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Philip Russel Taylor
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Eddie Chung Yern Wang
- Division of Infection & Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
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Collins FL, Williams JO, Bloom AC, Singh RK, Jordan L, Stone MD, McCabe LR, Wang ECY, Williams AS. CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss. Bone 2017; 97:94-104. [PMID: 28062298 PMCID: PMC5378198 DOI: 10.1016/j.bone.2017.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/23/2016] [Accepted: 01/03/2017] [Indexed: 12/11/2022]
Abstract
Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for death receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wt and DR3ko mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+ osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+ osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
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Affiliation(s)
- Fraser L Collins
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Jessica O Williams
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Anja C Bloom
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Ravinder K Singh
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Lauren Jordan
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michael D Stone
- University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff, United Kingdom
| | - Laura R McCabe
- Department of Physiology, Michigan State University, East Lansing, MI, USA; Department of Radiology, Michigan State University, East Lansing, MI, USA; Biomedical Imaging Research Centre, Michigan State University, East Lansing, MI, USA
| | - Eddie C Y Wang
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
| | - Anwen S Williams
- Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
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Collins FL, Schepper JD, Rios-Arce ND, Steury MD, Kang HJ, Mallin H, Schoenherr D, Camfield G, Chishti S, McCabe LR, Parameswaran N. Immunology of Gut-Bone Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1033:59-94. [PMID: 29101652 PMCID: PMC5749247 DOI: 10.1007/978-3-319-66653-2_5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In recent years a link between the gastrointestinal tract and bone health has started to gain significant attention. Dysbiosis of the intestinal microbiota has been linked to the pathology of a number of diseases which are associated with bone loss. In addition modulation of the intestinal microbiota with probiotic bacteria has revealed to have both beneficial local and systemic effects. In the present chapter, we discuss the intestinal and bone immune systems, explore how intestinal disease affects the immune system, and examine how these pathologic changes could adversely impact bone health.
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Affiliation(s)
- Fraser L Collins
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | | | - Naiomy Deliz Rios-Arce
- Department of Physiology, Michigan State University, East Lansing, MI, USA
- Comparative Medicine and Integrative Biology Program, East Lansing, MI, USA
| | - Michael D Steury
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Ho Jun Kang
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Heather Mallin
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Daniel Schoenherr
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Glen Camfield
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Saima Chishti
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Laura R McCabe
- Department of Physiology and Department of Radiology, Biomedical Imaging Research Centre, Michigan State University, East Lansing, MI, USA.
| | - Narayanan Parameswaran
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
- Comparative Medicine and Integrative Biology Program, East Lansing, MI, USA.
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Death Receptor 3 Promotes Chemokine-Directed Leukocyte Recruitment in Acute Resolving Inflammation and Is Essential for Pathological Development of Mesothelial Fibrosis in Chronic Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:2813-2823. [PMID: 27664471 DOI: 10.1016/j.ajpath.2016.07.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 06/20/2016] [Accepted: 07/19/2016] [Indexed: 12/19/2022]
Abstract
Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factor-like ligand TL1A (TNFSF15) control several processes in inflammatory diseases through the expansion of effector T cells and the induction of proinflammatory cytokines from myeloid and innate lymphoid cells. Using wild-type (DR3+/+) and DR3-knockout (DR3-/-) mice, we show that the DR3/TL1A pathway triggers the release of multiple chemokines after acute peritoneal inflammation initiated by a single application of Staphylococcus epidermidis supernatant, correlating with the infiltration of multiple leukocyte subsets. In contrast, leukocyte infiltration was not DR3 dependent after viral challenge with murine cytomegalovirus. DR3 expression was recorded on connective tissue stroma, which provided DR3-dependent release of chemokine (C-C motif) ligand (CCL) 2, CCL7, CXCL1, and CXCL13. CCL3, CCL4, and CXCL10 production was also DR3 dependent, but quantitative RT-PCR showed that their derivation was not stromal. In vitro cultures identified resident macrophages as a DR3-dependent source of CCL3. Whether DR3 signaling could contribute to a related peritoneal pathology was then tested using multiple applications of S. epidermidis supernatant, the repetitive inflammatory episodes of which lead to peritoneal membrane thickening and collagen deposition. Unlike their DR3+/+ counterparts, DR3-/- mice did not develop fibrosis of the mesothelial layer. Thus, this work describes both a novel function and essential requirement for the DR3/TL1A pathway in acute, resolving, and chronic inflammation in the peritoneal cavity.
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Williams JO, Wang ECY, Lang D, Williams AS. Characterization of death receptor 3-dependent aortic changes during inflammatory arthritis. Pharmacol Res Perspect 2016; 4:e00240. [PMID: 27347421 PMCID: PMC4915515 DOI: 10.1002/prp2.240] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 04/06/2016] [Accepted: 04/26/2016] [Indexed: 01/05/2023] Open
Abstract
Murine collagen-induced arthritis (mCIA) is characterized by decreased vascular constriction responses and increased MMP-9. Here, we describe additional histological alterations within the aorta and surrounding perivascular adipose tissue (PVAT), study the role of PVAT in constriction response, and investigate the potential involvement of death receptor 3 (DR3). mCIA was induced in wild-type (WT) and DR3-/- mice with nonimmunized, age-matched controls. Vascular function was determined in isolated aortic rings ±PVAT, using isometric tension myography, in response to cumulative serotonin concentrations. Cellular expression of F4/80 (macrophages), Ly6G (neutrophils), DR3, and MMP-9 was determined using immunohistochemistry. In WTs, arthritis-induced vascular dysfunction was associated with increased F4/80+ macrophages and increased DR3 expression in the aorta and PVAT. MMP-9 was also up-regulated in PVAT, but did not correlate with alterations of PVAT intact constriction. DR3-/- mice inherently showed increased leukocyte numbers and MMP-9 expression in the PVAT, but retained the same nonarthritic constriction response as DR3WT mice ±PVAT. Arthritic DR3-/- mice had a worsened constriction response than DR3WT and showed an influx of neutrophils to the aorta and PVAT. Macrophage numbers were also up-regulated in DR3-/- PVAT. Despite this influx, PVAT intact DR3-/- constriction responses were restored to the same level as DR3WT. Impaired vascular constriction in inflammatory arthritis occurs independently of total MMP-9 levels, but correlates with macrophage and neutrophil ingress. Ablating DR3 worsens the associated vasculature dysfunction, however, DR3-/- PVAT is able to protect the aorta against aberrant vasoconstriction caused in this model.
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Affiliation(s)
- Jessica O. Williams
- Division of Infection and ImmunityCardiff University School of MedicineCardiffUnited Kingdom
| | - Eddie C. Y. Wang
- Division of Infection and ImmunityCardiff University School of MedicineCardiffUnited Kingdom
| | - Derek Lang
- Division of Medical EducationCardiff University School of MedicineCardiffUnited Kingdom
| | - Anwen S. Williams
- Division of Infection and ImmunityCardiff University School of MedicineCardiffUnited Kingdom
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