Caspase-1 becomes activated in response to specific NLRP3 agonists, which results in the processing of pro-IL-1 into its mature secreted form. to include IgG-Ova immune complexes results in the suppression of CFA-induced Th17 responses and a concurrent enhancement of Ova-specific Th2 responses. Furthermore, we show the mechanism by which these immune complexes suppress Th17 responses is usually through the enhancement of IL-10 production. Acitretin In addition, the generation of Th17 responses following immunization with CFA and Ova were dependent on IL-1 but impartial of NLRP3 inflammasome activation. Together these data represent a novel mechanism by which the generation of Th17 responses is usually regulated. Introduction The CD4+ T cell response to an antigen is usually shaped by innate immune instruction reflecting the environment in which the antigen presenting cell (APC) initially encountered the antigen, including whether the antigen was associated with specific adjuvants or complexed with antibodies. Presentation of processed antigen with costimulatory molecules with precise combinations of cytokines drives the differentiation of na?ve CD4+ T cells down specific effector lineage pathways including T helper (Th) 1, Th2, or Th17. Circulating immune complexes are associated with both the initiation and the progression of many diseases and in particular autoimmune disorders. These IgG-immune complexes have been shown to be immunomodulatory and can regulate both innate and adaptive immune responses. Ligation of activating FcR on macrophages by IgG-immune complexes results in marked suppression of IL-12p40 production, a cytokine that plays a crucial role in Th1 differentiation . FcR ligation also induces the production of the anti-inflammatory cytokine IL-10 . Previous studies have exhibited that antigen-IgG immune complexes are capable of augmenting Th2 responses [3, 4] in part through their ability to modulate the production of the cytokines IL-12p40 and IL-10. However, the effect of IgG-immune complexes on Th17 responses is usually unknown. Th17 cells are typified by their elaboration of the proinflammatory cytokines IL-17A, IL-17F, and IL-22 and not only play a critical role in host defense against microbes but also drive the pathologic responses underlying autoimmune disorders . The production of the innate immune cytokines IL-6, TGF, IL-1 and IL-23 is required for the induction of pathogenic Th17 responses [5, 6]. IL-1R signaling in T cells has been shown to be critical for the generation of Th17 cells as mice deficient in IL-1R1 have a defect in the generation of Th17 responses in an experimental autoimmune encephalomyelitis (EAE) model with an associated reduction in disease severity [7, 8]. IL-1 and IL-1 are related cytokines that both signal through the IL-1R1, yet the individual contribution of IL-1 versus IL-1 to the generation of Th17 responses remains unclear. Despite sharing a common downstream receptor, the upstream regulation of IL-1 and IL-1 secretion occurs via distinct mechanisms. The NLRP3 inflammasome is usually a multiprotein complex composed of the NLR family member NLRP3, the adaptor molecule ASC, and the cysteine protease caspase-1 [9, 10]. Caspase-1 becomes activated in response to specific NLRP3 agonists, which results in the processing of pro-IL-1 into its mature secreted form. IL-1 secretion, in contrast, can occur in an NLRP3 inflammasome-dependent or impartial manner depending on the stimulus. Additionally, IL-1 can be released passively upon cell death and contribute Rabbit Polyclonal to EDG2 to sterile inflammatory responses. Although IL-1 can be cleaved, unlike IL-1, cleavage is not required for IL-1 to bind and signal through IL-1R1 . In this study we demonstrate Acitretin that this generation of CFA-induced Th17 responses was suppressed by antigen specific immune complexes. We show that while the CFA-induced Th17 response did require signaling through the IL-1R1, this signal was impartial Acitretin of NLRP3 inflammasome-driven IL-1 but was instead dependent upon IL-1. Dendritic cells that encountered antigen in an immune complex produced enhanced IL-10 while concurrently suppressing IL-1 production. This coordinated.
Caspase-1 becomes activated in response to specific NLRP3 agonists, which results in the processing of pro-IL-1 into its mature secreted form