The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE-associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission.

Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus

“…Since the first programmed cell death, apoptosis, described in 1972 by Kerr and his two colleagues [3], other programmed cell death pathways have been defined and intensively investigated, including NETosis, necroptosis, pyroptosis, and autophagy [4, 5]. Indeed, dysregulated cell death in combination with defective clearance of dying cells has been suggested to contribute to the release of damage-associated molecular patterns (DAMPs), amplification of inflammatory and immune responses, production and release of autoantigens, and tissue damage in SLE [6–8]. In this review, we discuss various forms of programmed cell death pathways with particular emphasis on inflammatory cell death such as NETosis, pyroptosis, and necroptosis and their consequences in the inflammatory and immune responses in SLE.…”

Disulfiram alleviates pristane-induced lupus via inhibiting GSDMD-mediated pyroptosis

“…SLE is a multifactorial systemic autoimmune disease, characterized by production of abundant autoantibodies [ 3 ]. Increasing evidence has demonstrated that dysregulated cell death and defective removal of dead cells underlie the onset of SLE [ 38 – 40 ]. In SLE patients, defective removal of dead cells contributes to the exposure of autoantigens and the release of damage-associated molecular patterns (DAMPs), thereby amplifying inflammation and immune responses [ 4 ].…”

Up-Regulated Expression of Pro-Apoptotic Long Noncoding RNA lincRNA-p21 in Lupus Nephritis Patients and an Experimental Mouse Model

“…LN has multiple pathogenic pathways including aberrant apoptosis, autoantibody production and IC deposition with complement activation [1,2]. Apoptotic cell death with roles in tissue damage and immune dysregulation, is involved in the generation of autoantigens and the externalization of modi ed nuclear antigens [3].…”

“…Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immune tolerance and formation of immune complexes (IC) containing nuclear autoantigens, resulting in in ammation at various organs and tissues, of which damage to the kidney as a consequence of lupus nephritis (LN) is the most common cause of morbidity and mortality [1,2]. Current understanding of the crucial pathogenic mechanisms includes an imbalance between production of apoptotic cells and disposal of apoptotic materials [2,3].…”

“…Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immune tolerance and formation of immune complexes (IC) containing nuclear autoantigens, resulting in in ammation at various organs and tissues, of which damage to the kidney as a consequence of lupus nephritis (LN) is the most common cause of morbidity and mortality [1,2]. Current understanding of the crucial pathogenic mechanisms includes an imbalance between production of apoptotic cells and disposal of apoptotic materials [2,3]. Notably, apoptotic cell death with ine cient clearance results in the accumulation of self-double strand DNA (dsDNA), followed by a break of tolerance to induce production of dsDNA antibody with IC deposition in glomerular and tubular basement membranes, contributing to the development of LN [3,4].…”