Abstract
Neutrophils are the most abundant leukocytes in circulation and represent one of the first lines of defense against invading pathogens. Neutrophils possess a vast arsenal of antimicrobial proteins, which can be released from the cell by a death program termed NETosis. Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed chromatin decorated with granular and cytosolic proteins. Both exuberant NETosis and impaired clearance of NETs have been implicated in the organ damage of autoimmune diseases, such as systemic lupus erythematosus (SLE), small vessel vasculitis (SVV), and psoriasis. NETs may also represent an important source of modified autoantigens in SLE and SVV. Here, we review the autoimmune diseases linked to NETosis, with a focus on how modified proteins externalized on NETs may trigger loss of immune tolerance and promote organ damage.
Highlights
Neutrophils are the most abundant leukocyte population in peripheral blood and have a lifespan of as little as 4 h in the circulation; this short half-life is balanced by continuous and tightly regulated release from the bone marrow
In 2004, Brinkmann et al described a distinct mechanism of neutrophil cell death, resulting in the programmed externalization of a meshwork of chromatin fibers decorated with granulederived antimicrobial proteins (Brinkmann et al, 2004)
The characterization of pathways implicated in the development of Neutrophil extracellular traps (NETs) has potential implications for pharmacologic strategies to block NETosis, which is appealing in the context of the “sterile” NETosis that will be described below
Summary
Neutrophils are the most abundant leukocyte population in peripheral blood and have a lifespan of as little as 4 h in the circulation; this short half-life is balanced by continuous and tightly regulated release from the bone marrow. MSU crystals, IL-1β, and both synovial fluid and serum from patients with acute gout, all stimulate neutrophils to release NETs (Mitroulis et al, 2011) These “gout NETs” contain DNA, MPO, and the alarmin, high mobility group box chromosomal protein 1 (HMGB1), and may propagate the inflammatory response. In terms of the NE protein, one study has suggested higher plasma levels in SLE patients (Zhang et al, 1989) Both the iron-chelator lactoferrin and the serine protease cathepsin G have been objectively identified in PMA-induced NETs (Urban et al, 2009), and both appear to function as autoantigens in SLE (Lee et al, 1992; Galeazzi et al, 1998; Zhao et al, 1998; Manolova et al, 2001; Caccavo et al, 2005); again, no clear clinical correlation has emerged. Α-defensins activate monocyte-lineage cells to release proinflammatory cytokines such as TNF-α and IL-1β; they serve as chemokines for recruitment of diverse cell types
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