Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis

Abstract

Nephritis is one of the most severe complications of systemic lupus erythematosus (SLE). One key characteristic of lupus nephritis (LN) is the deposition of immune complexes containing nucleic acids and/or proteins binding to nucleic acids and autoantibodies recognizing these molecules. A variety of cell death processes are implicated in the generation and externalization of modified nuclear autoantigens and in the development of LN. Among these processes, apoptosis, primary and secondary necrosis, NETosis, necroptosis, pyroptosis, and autophagy have been proposed to play roles in tissue damage and immune dysregulation. Cell death occurs in healthy individuals during conditions of homeostasis yet autoimmunity does not develop, at least in part, because of rapid clearance of dying cells. In SLE, accelerated cell death combined with a clearance deficiency may lead to the accumulation and externalization of nuclear autoantigens and to autoantibody production. In addition, specific types of cell death may modify autoantigens and alter their immunogenicity. These modified molecules may then become novel targets of the immune system and promote autoimmune responses in predisposed hosts. In this review, we examine various cell death pathways and discuss how enhanced cell death, impaired clearance, and post-translational modifications of proteins could contribute to the development of lupus nephritis.

Linking cellular stress responses to systemic homeostasis

“…Programmed cell death (PCD) culminates with efficient removal of cell corpses by tissue-resident macrophages coupled with the delivery of robust anti-inflammatory signals 148,149 . Conversely, RCD occurring in the context of failing adaptation to stress can be linked to the release of cellular content, including various pro-inflammatory signals 150 . The pro-inflammatory effects of RCD can underlie pathogenic maladaptation, as in the case of systemic lupus erythematosus (SLE) 150 .…”

Non‐erythropoietic erythropoietin‐derived peptide protects mice from systemic lupus erythematosus

“…53,54 In addition, monocyte chemoattractant protein (MCP-1) is implicated in the activation of inflammatory cells and has been suggested to affect the progression of lupus nephritis (LN). 55,56 Macrophages are the main origin of these inflammatory cytokines in SLE. In the current study, our in vivo and in vitro studies showed that ARA290 ameliorated inflammatory response in SLE mice and, notably, suppressed the expression of TNF-a, IL-6, iNOS and MCP-1 in macrophages, which suggested that ARA290 might alleviated the symptoms of SLE via regulating macrophage inflammatory response; however, the definite mechanism between ARA290 and macrophage inflammatory response needs further investigation.…”

The Gas6/TAM System and Multiple Sclerosis

“…However, while the underlying mechanisms have not been fully elucidated, an increase in anti-MOG antibody is observed under these circumstances [90]. Hence, impaired apoptosis also seems of significance in MS pathogenesis as it occurs for other systemic autoimmune diseases, such as systemic lupus erithematosus [91]. …”