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

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 αVß3 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.

Cadherin-11 and Its Role in Tissue Fibrosis.

Fibrosis is the excessive deposition of extracellular matrix that results from chronic inflammation and injury, leading to the loss of tissue integrity and function. Cadherins are important adhesion molecules that classically mediate calcium-dependent cell-to-cell adhesion and play important roles in tissue development and cellular migration but likely have functions beyond these important roles. Cadherin-11 (CDH11), a member of the cadherin family, has been implicated in several pathological processes including cancer. More recent evidence suggests that CDH11 is a central mediator of tissue fibrosis. CDH11 expression is increased in patients with fibrotic diseases such as idiopathic pulmonary fibrosis and systemic sclerosis. CDH11 expression is increased in mouse models of lung, skin, liver, cardiac, renal, and intestinal fibrosis. Targeting CDH11 in murine models of fibrosis clearly demonstrates that CDH11 is a common mediator of fibrosis across multiple tissues. Insight into potential mechanisms at the cellular and molecular level is emerging. In this review, we present the evolving evidence for the involvement of CDH11 in tissue fibrosis. We also discuss some of the proposed mechanisms and highlight the potential of CDH11 as a common therapeutic target and biomarker in different fibrotic pathologies.

Targeting type I interferons in systemic lupus erythematous.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for the treatment of certain manifestations of SLE. In the current narrative review, we will discuss the role of type I IFN in SLE pathogenesis and the potential translation of these data into strategies using type I IFN as a biomarker and therapeutic target for patients with SLE.

Cadherin-11 Regulates Macrophage Development and Function.

Cadherin-11 (CDH11) is a cell-cell adhesion protein that has previously been reported to play an important role in the pathogenesis of pulmonary fibrosis. It is expressed on macrophages in the fibrotic lung. However, the role of CDH11 on macrophage biology has not yet been studied. We show using immunophenotypic analyses that Cdh11-/- mice have fewer recruited monocyte-derived macrophages and Ly6Chi monocytes in the lungs compared to wild-type mice in the intraperitoneal bleomycin-induced pulmonary fibrosis model. Additionally, fewer Ly6Chi monocytes were detected in the bone marrow and peripheral blood of naive Cdh11-/- mice. Given that macrophages are derived from monocytes, we investigated the precursors of the monocyte/macrophage lineage in the bone marrow. We found increased numbers of CMPs and reduced numbers of GMPs and MPs/cMoPs in Cdh11-/- mice compared to wild-type mice, suggesting decreased differentiation towards the myeloid lineage in Cdh11-/- mice. Furthermore, we show using bone marrow cells that loss of CDH11 impaired monocyte to macrophage differentiation. We also demonstrate that CDH11 deficiency repressed the M2 program and impaired the phagocytic function of bone marrow-derived macrophages. Overall, our findings demonstrate a role for CDH11 in macrophage development, M2 polarization, and phagocytic function.