Leukotriene B 4 licenses inflammasome activation to enhance skin host defense

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-1β and IL-18 in addition to inducing a type of inflammatory cell death termed "pyroptosis." Leukotriene B 4 (LTB 4 ) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB 4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB 4 is required for the expression of pro-IL-1β and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB 4 -mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1β-enhanced skin host defense. Together, these data unveil a new role for LTB 4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB 4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB 4 can be used as an adjuvant to boost inflammasome-dependent host defense.