Leukotriene B 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 (LTB) 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 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB is required for the expression of pro-IL-1β and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB-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 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB can be used as an adjuvant to boost inflammasome-dependent host defense.