期刊
FRONTIERS IN IMMUNOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02519
关键词
caspase-11; gout; neutrophils; macrophages; NETosis; IL-1 beta; cell migration; inflammasome
类别
资金
- Cystic Fibrosis Foundation Post-doctoral Research Fellowship
- Deutsche Forschungsgemeinschaft (DFG-German Research Foundation)
- Cystic Fibrosis Foundation (CFF)
- Cure Cystic Fibrosis Columbus Training grant
- Egyptian Cultural and Educational bureau
- Cystic Fibrosis Foundation [PARTID18P0]
- National Center for Advancing Translational Sciences [UL1TR001070]
- Taawon Welfare Association, West Bank, Palestine
- Bank of Palestine
- [R21 AI113477]
- [R01 AI124121]
- [R01 HL094586]
- [R01 HL076278]
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-1 beta 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-1 beta, TNF alpha, IL-6, and KC, while others like IFN gamma and IL-12p70 are not altered. IL-1 beta 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.
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