Role of Interleukin 36γ in Host Defense Against Tuberculosis

Tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. The roles of the interleukin 1 (IL-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. In contrast, the regulation of interleukin 36 gamma (IL-36 gamma), a recently described member of the IL-1 family, and its immunological relevance in host defense remain largely unknown. Here we show that Mycobacterium tuberculosis infection of macrophages induces IL-36 gamma production in a 2-stage-regulated fashion. In the first stage, microbial ligands trigger host Toll-like receptor and MyD88-dependent pathways, leading to IL-36 gamma secretion. In the second stage, endogenous IL-1 beta and interleukin 18 further amplify IL-36 gamma synthesis. The relevance of this cytokine in the control of M. tuberculosis is demonstrated by IL-36 gamma-induced antimicrobial peptides and IL-36 receptor-dependent restriction of M. tuberculosis growth. Thus, we provide first insight into the induction and regulation of the proinflammatory cytokine IL-36 gamma during tuberculosis.