Caspase-11 Mediates Neutrophil Chemotaxis and Extracellular Trap Formation During Acute Gouty Arthritis Through Alteration of Cofilin Phosphorylation

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.

Pyroptotic and non‐pyroptotic effector functions of caspase‐11

“…Knockdown of caspase‐5 reduces IL‐1α release and cytokines associated with SASP such as IL‐6, MCP1, and IL‐8, suggesting that caspase‐5 is required for IL‐1α release during senescence in vitro. We also showed that IL‐6, KC, and TNF‐α are drastically reduced in the absence of caspase‐11 33 . Additionally, caspase‐11 −/− mice showed reduction in the level of IL‐1α and KC in response to MRSA infection 60 .…”

“…Recent study showed that at sublytic levels of inflammasome activation, and in the absence of pyroptotic cell death, gasdermin D pores mediate the release of IL‐1β or IL‐18 and other cytosolic proteins 84 . Notably, we have shown that the release of IL‐1β from macrophages in response to MSU was not accompanied by cell death 33 . Our findings are corroborated by recent reports describing how gasdermin forms pores within the intact plasma membrane, allowing the release of IL‐1β independently of cell death 85,86 .…”

“…HMGB1 utilizes a variety of receptors to promote its signaling events, and LPS is sensed by TLR4, which uses both adapters to signal 35,36 . We have shown that caspase‐11 expression was not significantly hampered in the WT or the single knockout macrophages during stimulation with either HMGB1 or LPS, except when both MYD88 and TRIF were absent, indicating that either adapter was able to countervail for the deficient one in order to induce caspase‐11 33 . Certain diseases have been classified as an IL‐1β‐mediated condition such as gout since neutralizing antibodies to IL‐1β or the caspase‐1 inhibitor z‐YVAD significantly reduce inflammation and the production of other cytokines within the joints 37‐39 .…”

“…Recently, we have demonstrated that expression of caspase‐11 is induced by IL‐1β and IL‐1α via the IL‐1R/MYD88 33 . Indeed, single myd88 −/− , trif −/− , and myd88/ trif −/− , macrophages, 34 showed reduced caspase‐11 expression in response to IL‐1α and IL‐1β, or in combination, respectively 33 . Additionally, we have revealed that induction of caspase‐11 by LPS and HMGB1 is independent of IL‐1R.…”

“…Induction of caspase‐11 expression by released IL‐1β and IL‐1α could prime immune cells for inflammasome activation by subsequent insults including monosodium urate (MSU). Thus, preventing the expression of caspase‐11 in gout‐prone individuals may prevent the instigation of tissue damage 33 . Additionally, we have shown that house dust mites (HDM) induce caspase‐11 expression in bone marrow‐derived macrophages and in C57BL/6 mice (Abu Khweek et al under review).…”