Neutrophils in the Pathogenesis of Rheumatic Diseases: Fueling the Fire
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Neutrophils in the Pathogenesis of Rheumatic Diseases: Fueling the Fire Yudong Liu1 · Mariana J. Kaplan2 Accepted: 27 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Systemic rheumatic diseases are a heterogeneous group of disorders characterized by profound immune dysregulation. Recent discoveries have led to a significant resurgence of interest in neutrophils as shapers of immune dysregulation and as triggers of organ damage in rheumatic diseases. Neutrophils contribute to the initiation, promotion, and perpetuation of immune dysregulation through a variety of mechanisms including synthesis of proinflammatory cytokines, direct tissue damage through degranulation and synthesis of reactive oxygen species, and the formation of neutrophil extracellular traps (NETs). The identification of a subset of proinflammatory neutrophils, the low-density granulocytes (LDGs), which promote Th1 responses and cause endothelial dysfunction, has further strengthened the pathogenic role of neutrophils in various rheumatic diseases. The presence of autoantibodies targeting molecules commonly expressed in neutrophils suggests that neutrophils, particularly NETs, may be a source of autoantigens. An imbalance between NET formation and degradation, which leads to increased NET levels in the circulation and tissues, could enhance the exposure of the immune system to modified autoantigens, promote vascular disease, and increase tissue damage. This review will present an overview of recent advances in our understanding of how neutrophil dysregulation modulates the innate and adaptive immune responses in systemic rheumatic diseases and their putative contributions to pathogenicity. Understanding the potential pathogenic role of neutrophil dysregulation may provide better molecular candidates for therapeutic targeting, and ultimately promote improvements in the clinical outcomes in rheumatic diseases. Keywords Neutrophils · Neutrophil extracellular traps · Low-density granulocytes · Rheumatic diseases · Autoimmunity
Introduction Systemic rheumatic diseases represent a heterogeneous group of disorders with a multifactorial etiology [1]. The hallmark of systemic autoimmune diseases is profound immune dysregulation, characterized by a loss of immune tolerance to a wide variety of autoantigens and dysregulated * Yudong Liu [email protected] * Mariana J. Kaplan [email protected] 1
Department of Clinical Laboratory, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China
Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, 12N248C, Bethesda, MD, USA
2
innate and adaptive immune responses [2]. Over the last decade, dramatic progress has been achieved toward understanding how aberrant immunity contributes to organ inflammation and damage in rheumatic diseases. The wide spectrum of clinical manifestations in rheum
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