NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense

(Franchi et al., Nature Immunology 2012, 13:449-457)

Speaker: Meng-Hsuan Tsai (蔡孟暄)                    Time: 13:00~14:00, Dec. 05, 2012

Commentator: Dr. Pei-Jane Tsai (蔡佩珍老師)    Place: Room 601

Abstract

        Innate immune cells recognize bacteria by using Toll-like receptors (TLRs) and Nod-like receptors (NLRs) and produce pro-inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF) and IL-1β, to induce the anti-bacterial inflammatory response. In intestines, the inflammatory response is induced by pathogenic bacteria but not by commensal bacteria, while the underlying mechanism remains unclear. In this study, the authors showed that intestnal mononuclear phagocytes (iMPs), the key immune cells regulating intestinal homeostasis and inflammation, differentially responded to these two groups of bacteria. Unlike bone marrow-derived macrophages (BMDMs), iMPs did not produce IL-6 and TNF when treated with TLR ligands or various bacteria but they constitutively expressed pro-IL-1β in the absence of priming signals. Activation of caspase 1, cleavage of pro-IL-1β and production of mature IL-1β in iMPs were readily induced by pathogenic bacteria but not by the commensals. These induction events required NLRC4 inflammasome of iMPs and the type III secretion system (T3SS) and flagellin of pathogenic Salmonella. Furthermore, Nlrc4^-/- or Il1r^-/- BALB/c mice were more susceptible to intestianal Salmonella infection than wild-type mice, showing weaker intestinal inflammation, lower recruitemnt of neutrophils, higher bacterial load, and poorer survival after the infection. In summary, iMPs are hyporesponsive to TLR stimulation for maintenance of intestinal homeostasis, but they can use NLRC4 inflammasome for sensing factors specifically expressed by pathogenic bacteria. Thus the NLRC4─IL-1 axis is the critical response for protection of the host from intestinal infection.

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