Abstract
Gouty arthritis results from the generation of monosodium urate (MSU) crystals within joints. These MSU crystals elicit acute inflammation characterized by massive infiltration of neutrophils and monocytes that are mobilized by the pro-inflammatory cytokine IL-1β. MSU crystals also activate the complement system, which regulates the inflammatory response; however, it is unclear whether or how MSU-mediated complement activation is linked to IL-1β release in vivo, and the various roles that might be played by individual components of the complement cascade. Here we show that exposure to MSU crystals in vivo triggers the complement cascade, leading to the generation of the biologically active complement proteins C3a and C5a. C5a, but not C3a, potentiated IL-1β and IL-1α release from LPS–primed MSU-exposed peritoneal macrophages and human monocytic cells in vitro; while in vivo MSU–induced C5a mediated murine neutrophil recruitment as well as IL-1β production at the site of inflammation. These effects were significantly ameliorated by treatment of mice with a C5a receptor antagonist. Mechanistic studies revealed that C5a most likely increased NLRP3 inflammasome activation via production of reactive oxygen species (ROS), and not through increased transcription of inflammasome components. Therefore we conclude that C5a generated upon MSU-induced complement activation increases neutrophil recruitment in vivo by promoting IL-1 production via the generation of ROS, which activate the NLRP3 inflammasome. Identification of the C5a receptor as a key determinant of IL-1-mediated recruitment of inflammatory cells provides a novel potential target for therapeutic intervention to mitigate gouty arthritis.
Highlights
Gout is the most common form of inflammatory arthritis and is associated with a substantial public health burden (Rees et al, 2014)
In the absence of monosodium urate (MSU) crystals, LPS alone, LPS and C3a, LPS and C5a did not induce the release of IL-1β and IL-1α (Figures 1A,B); while the addition of MSU crystals triggered the release of both IL-1α and IL-1β from macrophages (Figures 1A,B)
C5a is a potent mediator of the inflammatory response as a result of its ability, upon engagement of C5a receptors, to regulate vasodilation and to mediate chemotaxis and activation of inflammatory leukocytes
Summary
Gout is the most common form of inflammatory arthritis and is associated with a substantial public health burden (Rees et al, 2014). IL-1 plays a pivotal role in gout-associated inflammation by instigating the release of multiple pro-inflammatory cytokines and chemokines (IL-8, IL6, CXCL8, CXCL1), and the upregulation of adhesion molecules (selectins, integrins) on endothelial cells, which directly induces a massive infiltration of inflammatory cells (i.e., neutrophils and monocytes) at the site of crystal deposition (Brown et al, 1994; Hachicha et al, 1995). Prolonged accumulation of these cells can result in irreversible destruction of joint tissues and increases the risk of chronic inflammation. Therapies directed toward mitigating MSU-induced neutrophil infiltration and activation may be beneficial for gout patients
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