Abstract
Gout is characterized by attacks of arthritis with hyperuricemia and monosodium urate (MSU) crystal-induced inflammation within joints. Innate immune responses are the primary drivers for tissue destruction and inflammation in gout. MSU crystals engage the Nlrp3 inflammasome, leading to the activation of caspase-1 and production of IL-1β and IL-18 within gout-affected joints, promoting the influx of neutrophils and monocytes. Here, we show that caspase-11−/− mice and their derived macrophages produce significantly reduced levels of gout-specific cytokines including IL-1β, TNFα, IL-6, and KC, while others like IFNγ and IL-12p70 are not altered. IL-1β induces the expression of caspase-11 in an IL-1 receptor-dependent manner in macrophages contributing to the priming of macrophages during sterile inflammation. The absence of caspase-11 reduced the ability of macrophages and neutrophils to migrate in response to exogenously injected KC in vivo. Notably, in vitro, caspase-11−/− neutrophils displayed random migration in response to a KC gradient when compared to their WT counterparts. This phenotype was associated with altered cofilin phosphorylation. Unlike their wild-type counterparts, caspase-11−/− neutrophils also failed to produce neutrophil extracellular traps (NETs) when treated with MSU. Together, this is the first report demonstrating that caspase-11 promotes neutrophil directional trafficking and function in an acute model of gout. Caspase-11 also governs the production of inflammasome-dependent and -independent cytokines from macrophages. Our results offer new, previously unrecognized functions for caspase-11 in macrophages and neutrophils that may apply to other neutrophil-mediated disease conditions besides gout.
Highlights
Gout is an ancient disease that is estimated to affect 8.3 million people in the United States, and this number is steadily increasing [1]
Real-time quantitative (RT) PCR analysis performed on RNA isolated from joint samples revealed that monosodium urate (MSU) significantly induced the expression of caspase-11 mRNA in vivo, compared to the vehicle (PBS)treated joints (Supplementary Figure 2)
Inflammatory cytokine release, tissue damage, and remodeling in gout have been linked to the activation of the Nlrp3 inflammasome in response to MSU [11]
Summary
Gout is an ancient disease that is estimated to affect 8.3 million people in the United States, and this number is steadily increasing [1]. Inflammasome-dependent cytokines, interleukin-1 beta (IL-1β), and interleukin-18 (IL-18) are released, activating interstitial cells and promoting influx of polymorphonuclear cells (PMNs—neutrophils), monocytes, and macrophages [11, 13] Release of these cytokines in gout induces the differentiation of osteoclasts from mononuclear precursors and stimulates bone resorption [14, 15]. Within the affected joint space, immune cells release other pro-inflammatory cytokines like TNFα, IL-6, and IL-8 (CXCL1/KC); eicosanoid lipid mediators; and production of the enzymes collagenase and stromelysin that degrade the extracellular matrix in articular structures This causes a cascade of cytotoxic cellular contents and danger-associated molecular patterns (DAMPs) to leak into extracellular venues and recruit other immune cells, producing more inflammation and tissue destruction [11, 18]. NETs orchestrate the initiation and progression of inflammation in gout [8, 20, 23]
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