Abstract
Loss of tolerance to nuclear antigens and multisystem tissue destruction is a hallmark of systemic lupus erythematosus (SLE). Although the source of autoantigen in lupus remains elusive, a compelling hypothetical source is dead cell debris that drives autoimmune activation. Prior reports suggest that neutrophil extracellular traps (NETs) and their associated death pathway, NETosis, are sources of autoantigen in SLE. However, others and we have shown that inhibition of NETs by targeting the NADPH oxidase complex and peptidylarginine deiminase 4 (PADI4) did not ameliorate disease in spontaneous murine models of SLE. Furthermore, myeloperoxidase and PADI4 deletion did not inhibit induced lupus. Since NET formation may occur independently of any one mediator, to address this controversy, we genetically deleted an additional important mediator of NETs and neutrophil effector function, neutrophil elastase (ELANE), in the MRL.Faslpr model of SLE. ELANE deficiency, and by extension ELANE-dependent NETs, had no effect on SLE nephritis, dermatitis, anti-self response, or immune composition in MRL.Faslpr mice. Taken together with prior data from our group and others, these data further challenge the paradigm that NETs and neutrophils are pathogenic in SLE.
Highlights
systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the formation of autoantibodies to nucleic acids and the proteins to which these nucleic acids associate [1]
Others and we have shown that inhibition of neutrophil extracellular traps (NETs) by targeting the NADPH oxidase complex and peptidylarginine deiminase 4 (PADI4) did not ameliorate disease in spontaneous murine models of SLE
The data from the genetic study presented here in a relevant murine model of lupus does not support the hypothesis that ELANE, and by extension ELANE-dependent NET generation and neutrophil effector function, alters immune system composition or pathology in SLE
Summary
SLE is a systemic autoimmune disease characterized by the formation of autoantibodies to nucleic acids and the proteins to which these nucleic acids associate [1]. Loss of tolerance to self-antigens results in immune activation and tissue destruction [1]. The origin of autoantigens in SLE are not known, the liberation of antigenic contents from dying cells is considered a likely culprit. Neutrophils are postulated to play a critical role in SLE pathogenesis by secreting proinflammatory cytokines, directly mediating end organ injury, and by forming neutrophil extracellular traps (NETs) [2]. NETs are extruded DNA structures coated with granular and cytoplasmic contents that are released into the extracellular environment. There is substantial disagreement and controversy about the definition of a NET, how to detect and quantify
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