Author ORCID Identifier
N/A
https://orcid.org/0000-0002-9323-9437
https://orcid.org/0000-0001-5583-9194
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https://orcid.org/0000-0001-7740-4685
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https://orcid.org/0000-0002-6288-4927
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https://orcid.org/0000-0002-9046-4647
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https://orcid.org/0000-0003-2996-9440
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Document Type
Article
Publication Date
2019
College/Unit
School of Medicine
Department/Program/Center
Microbiology, Immunology, and Cell Biology
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.
Digital Commons Citation
Caution, Kyle; Young, Nicholas; Robledo-Avila, Frank; Krause, Kathrin; Khweek, Arwa Abu; Hamilton, Kaitlin; Badr, Asmaa; Vaidya, Anup; Daily, Kylene; Gosu, Hawin; Anne, Midhun N. K.; Eltobgy, Mostafa; Dakhlallah, Duaa; Argwal, Sudha; Estfanous, Shady; Zhang, Xiaoli; Partida-Sanchez, Santiago; Gavrilin, Mikhail A.; Jarjour, Wael N.; and Amer, Amal O., "Caspase-11 Mediates Neutrophil Chemotaxis and Extracellular Trap Formation During Acute Gouty Arthritis Through Alteration of Cofilin Phosphorylation" (2019). Faculty & Staff Scholarship. 1505.
https://researchrepository.wvu.edu/faculty_publications/1505
Source Citation
K, Young N, Robledo-Avila F, Krause K, Abu Khweek A, Hamilton K, Badr A, Vaidya A, Daily K, Gosu H, Anne MNK, Eltobgy M, Dakhlallah D, Argwal S, Estfanous S, Zhang X, Partida-Sanchez S, Gavrilin MA, Jarjour WN and Amer AO (2019) Caspase-11 Mediates Neutrophil Chemotaxis and Extracellular Trap Formation During Acute Gouty Arthritis Through Alteration of Cofilin Phosphorylation. Front. Immunol. 10:2519. doi: 10.3389/fimmu.2019.02519
Comments
Copyright © 2019 Caution, Young, Robledo-Avila, Krause, Abu Khweek, Hamilton, Badr, Vaidya, Daily, Gosu, Anne, Eltobgy, Dakhlallah, Argwal, Estfanous, Zhang, Partida-Sanchez, Gavrilin, Jarjour and Amer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.