CADHERIN-11 regulation of myeloid phagocytes and autoimmune inflammation in murine lupus.

Autor: Chavula T; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA., To S; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Smith J; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Pedroza M; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Nimri J; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Devaraj S; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Pathology Department, Texas Children's Hospital, Houston, TX, USA., Wenderfer S; Department of Pediatric Nephrology, B.C. Children's Hospital, Vancouver, BC, Canada., Vogel TP; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics-Rheumatology, Baylor College of Medicine, Houston, TX, USA; Division of Rheumatology, Texas Children's Hospital, Houston, TX, USA., Agarwal SK; Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: skagarwa@bcm.edu.
Jazyk: angličtina
Zdroj: Journal of autoimmunity [J Autoimmun] 2024 May; Vol. 145, pp. 103197. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1016/j.jaut.2024.103197
Abstrakt: Background and Objective: Understanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation.
Methods: We analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11 -/- mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls.
Results: Using bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh11 -/- mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVβ3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo, Cdh11-/- mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11-/- mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11-/- mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls.
Conclusion: This study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11 -/- mice developed decreased tissue inflammation and damage.
Competing Interests: Declaration of competing interest The authors declare that no potential conflicts of interest exist.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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