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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02519

Caspase-11 mediates neutrophil chemotaxis and extracellular trap formation during acute gouty arthritis through alteration of cofilin phosphorylation

Kyle Caution1,  Nicholas A. Young1,  Frank Robledo Avila2,  Kathrin Krause1,  Arwa Abu Khweek1, 3, kaitlin Hamilton1,  Asmaa Badr1, Anup Vaidya1,  Kylene Daily1, Hawin Gosu1, Midhun Anne1, Mostafa Eltobgy1,  Duaa Dakhlallah4, Sudha Argwal1,  Shady Estfanous1,  Xiaoli Zhang1,  Santiago Partida Sanchez5,  Mikhail A. Gavrilin1,  Wael Jarjour1 and  Amal O. Amer6*
  • 1The Ohio State University, United States
  • 2Nationwide Children's Hospital, United States
  • 3Department of Biology and Biochemistry, Birzeit University, Palestine
  • 4West Virginia University, United States
  • 5The Research Institute at Nationwide Children's Hospital, United States
  • 6Microbial Infection and Immunity, College of Medicine, The Ohio State University, United States

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. In neutrophils, the absence of caspase-11 reduced the ability of 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 counter parts, 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.

Keywords: Inflammation, macrophages & neutrophils, Inflammasome, Gout, cytokine, Arthritis

Received: 16 Jul 2019; Accepted: 09 Oct 2019.

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.

* Correspondence: Dr. Amal O. Amer, Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, United States,