Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1b via a noncanonical caspase-8 inflammasome

Gringhuis S.I., et al. 2012. Nat. Immunol. 13: 246-54

Speaker: Shu-Ting Lu (呂淑婷)                            Time: 14:00~15:00, May. 2, 2012

Commentator: Dr. Pin Ling(凌  斌 老師)          Place: Room 601

Abstract:

Dectin-1 is expressed mainly in dendritic cells (DC) and macrophages and recognizes β-glucans, the major cell wall component of fungi including Candida albicans and Aspergillus fumigatus. Dectin-1 also interacts with Mycobacterium spp. Upon ligand binding, spleen tyrosine kinase (Syk) is recruited to the Dectin-1 and triggers the CARD9, Bcl-10 and MALT1 complex formation and subsequently activates NF-κB pathway, resulting in the activation of various genes including those encoding pro-inflammatory cytokines (1). Interleukin 1β (IL-1β) is an important proinflammatorycytokine involved in inflammatory and antimicrobial activities, include antifungal defense. DC have been indicated to facilitate the differentiation of IL-17-producing helper T cells (TH17 cells) by releasing IL-1β, further mobilizing neutrophils to defense against fungal infection (2). However, the detail mechanism of fungi trigger DC to product IL-1β is still unknown. Bioactive IL-1β is as the result of cleavage from pro-IL-1β, which is responsible by caspase-1-dependent inflammasome. In this study, the authors found a new noncanonical caspase-8 inflammasome which mediates pro-IL-1β processing through dectin-1 signaling. All fungal and mycobacteria recognized by dectin-1 trigger MALT-1-caspase-8 complex recruiting to CARD9-Bcl-10-MALT1 scaffold companied by ASC. In contrast to caspase-1-dependent inflammasome, noncanonical caspase-8 inflammasomedoesn’t required internalization of pathogens, and can directly be activated by extracellular Dectin-1. Dectin-1 signaling triggers the ability of noncanonical caspase-8 inflammasome processing pro-IL-1β, provides a potential to induce downstream protective immunity to not only fungal but also mycobacterial infection.

References:

1.      Gringhuis, S.I., et al. 2009 Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat. Immunol. 10, 203-213

2.      Di Cesare A., et al 2009 The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J. Invest. Dermatol. 129, 1339-50.