Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production, inflammation, and immune complex deposition leading to tissue damage in the skin, joints, and kidneys [1]. Treatment options are limited in efficacy with significant risk of adverse effects. Therefore, understanding disease pathogenesis in SLE is a critical area of research to identify potential therapeutic targets.

The clearance of apoptotic cells, called efferocytosis, by dendritic cells (DCs) and macrophages maintains homeostasis and prevents inflammation. Inefficient efferocytosis results in accumulation of apoptotic debris which undergo secondary necrosis, releasing self-antigens that break tolerance in autoimmune diseases like SLE [[2], [3]]. Macrophages and DCs from SLE patients have impaired efferocytosis [[4], [5], [6]] and mice deficient in efferocytosis develop widespread autoimmunity in vivo [[7], [8], [9]]. Therefore, understanding the regulation of efferocytosis is crucial for understanding autoimmunity and SLE pathogenesis.

Cadherin-11 (CDH11) is a type 2 cadherin that primarily mediates cell adhesion and also regulates cell migration and differentiation [10,11]. Murine studies have demonstrated that CDH11 modulates tissue inflammation in mouse models of synovial inflammation [12] and tissue fibrosis in the skin, lung, and liver [[13], [14], [15], [16]]. These findings have relevance to patients with rheumatoid arthritis (RA) and systemic sclerosis (SSc) who have increased CDH11 levels [17,18]. The involvement of CDH11 in SLE has not been examined.

Research on CDH11 has focused on mesenchymal cells but multiple studies now show CDH11 expression and regulation of myeloid cells such as macrophages [15,16,19,20]. Recently, a novel role of CDH11 in regulating phagocytosis in macrophages was reported [21]. Bone marrow-derived macrophages (BMDMs) from Cdh11−/− mice had defective phagocytosis. However, the extent and mechanism of this regulation is unknown. This warrants further investigation given that macrophage and DC phagocytosis have significant implications in autoimmune inflammation.

Our objective was to investigate the extent to which CDH11 regulates myeloid cell function and we hypothesized that CDH11 deficiency impairs efferocytosis and promotes autoimmunity and systemic inflammation in murine lupus. We conducted in vitro and in vivo efferocytosis analysis in macrophages and DCs and examined disease development in vivo in pristane-induced lupus. To translate the relevance of CDH11 to human disease, we analyzed CDH11 expression in SLE patients.