Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Pathology Department, Texas Children's Hospital, Houston, TX, USA.
J Autoimmun. 2024 May;145:103197. doi: 10.1016/j.jaut.2024.103197. Epub 2024 Mar 5.
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.
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.
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.
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.
理解髓样吞噬细胞清除作用的调控对于确定系统性红斑狼疮（SLE）中的新靶点非常重要。钙黏蛋白 11（CDH11）是一种细胞黏附分子，它与炎症性关节炎和纤维化有关，最近被证明可以调节巨噬细胞吞噬作用。但是这种调节的程度和机制尚不清楚。我们的目的是研究 CDH11 调节髓样吞噬细胞的程度以及其对自身免疫和组织炎症的贡献。
我们分析了 WT 和 Cdh11 小鼠的巨噬细胞和树突状细胞（DC）中的吞噬作用，并在体外研究了相关机制。我们在体内使用角鲨烷诱导的狼疮模型研究了 CDH11 在疾病发展中的作用。为了将 CDH11 在人类疾病中的临床相关性转化为实际应用，我们在两个独立的儿科 SLE（pSLE）队列和健康对照中测量了血清 CDH11 水平。
我们使用骨髓来源的巨噬细胞（BMDM）和树突状细胞（BMDC）发现，Cdh11 小鼠的吞噬细胞吞噬作用受损，这是由吞噬作用受体表达和 RhoGTPase 激活下调介导的。具体来说，CDH11 缺失会下调 BMDM 中的 Mertk 表达和 Rac1 激活，并下调 BMDC 中的整合素 αVβ3 表达和 Cdc42 激活，突出了不同的途径。在体内，Cdh11-/- 小鼠表现出清除作用缺陷和凋亡碎片在角鲨烷诱导的狼疮中的积累增加。此外，Cdh11-/- 小鼠的全身炎症和自身免疫炎症增强，表现为抗 dsDNA 自身抗体增加、脾肿大、I 型干扰素和炎症细胞因子增加。矛盾的是，在组织水平上，Cdh11-/- 小鼠对肾小球肾炎有保护作用，表明其在小鼠狼疮中具有双重作用。最后，SLE 患者的血清 CDH11 水平高于对照组。
本研究强调了 CDH11 在调节髓样细胞和吞噬作用中的新作用及其作为自身免疫性小鼠狼疮发展的潜在贡献。尽管自身免疫性增加，Cdh11 小鼠的组织炎症和损伤减少。
