Leukotriene B4 licenses inflammasome activation to enhance skin host defense.

ABSTRACT

The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1ß and IL-18 in addition to inducing a type of inflammatory cell death termed "pyroptosis." Leukotriene B4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1ß and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB4-mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1ß-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense.