An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells

Abstract

Dendritic cells (DCs) utilize pattern recognition receptors to detect microorganisms and activate protective immunity. These cells and receptors are thought to operate in an all-or-none manner, existing in an immunologically active or inactive state. Here, we report that encounters with microbial products and self-encoded oxidized phospholipids (oxPAPC) induce an enhanced DC activation state, which we call “hyperactive.” Hyperactive DCs induce potent adaptive immune responses and are elicited by caspase-11, an enzyme that binds oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. Both lipids induce caspase-11–dependent interleukin-1 release, but only LPS induces pyroptosis. The cells and receptors of the innate immune system can therefore achieve different activation states, which may permit context-dependent responses to infection.

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States

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Inflammasome Priming in Sterile Inflammatory Disease

“…Indeed, oxPAPC (oxidized phospholipid) species may constitute a structural mimetic of LPS and directly bind to caspase-11 [134]. More data are required to validate this in relevant metabolic models where oxPAPC may be pathogenic, and these might then highlight sterile inflammatory conditions for which priming of non-canonical inflammasomes is mediated by endogenous factors through IFN.…”

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

“…Caspase-11-deficient mice were protected in endotoxemic shock (10,11), suggesting that in the setting of an overwhelming inflammatory response, the potentially protective pyroptotic mechanism activates an exaggerated pathologic response due to overwhelming cell lysis. The role of the inflammatory caspases 4/5/11 in mediating cytoplasmic LPS signaling and pyroptosis has until now been primarily studied in macrophages or dendritic cells (11,12,14,28,32,36). Their role in destroying the endothelial barrier through widespread endothelial death and pathogenesis of ALI remains unknown.…”