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Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis.

ABSTRACT: Allergic asthma is a chronic inflammatory disorder of the airways that affects >300 million people worldwide. The pro-inflammatory cytokines interleukin (IL)-1? and IL-1? have essential roles in the pathogenesis of asthma. However, the mechanisms underlying the production of IL-1 cytokines in allergic asthma remain unclear. In this study, we used a mouse model of ovalbumin-induced asthma to identify a crucial role for caspase-8 in the development of allergic airway inflammation. We further demonstrated that hematopoietic cells have dominant roles in caspase-8-mediated allergic airway inflammation. Caspase-8 was required for the production of IL-1 cytokines to promote Th2 immune response, which promotes the development of pulmonary eosinophilia and inflammation. Thus, our study identifies caspase-8 as a master regulator of IL-1 cytokines that contribute to the pathogenesis of asthma and implicates caspase-8 inhibition as a potential therapeutic strategy for asthmatic patients.

SUBMITTER: Qi X

PROVIDER: S-EPMC5035164 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis.

Qi X X Gurung P P Malireddi R K S RK Karmaus P W F PW Sharma D D Vogel P P Chi H H Green D R DR Kanneganti T-D TD

Mucosal immunology 20160323 1

Allergic asthma is a chronic inflammatory disorder of the airways that affects >300 million people worldwide. The pro-inflammatory cytokines interleukin (IL)-1α and IL-1β have essential roles in the pathogenesis of asthma. However, the mechanisms underlying the production of IL-1 cytokines in allergic asthma remain unclear. In this study, we used a mouse model of ovalbumin-induced asthma to identify a crucial role for caspase-8 in the development of allergic airway inflammation. We further demon ...[more]

PMID: 27007676

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Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1? (IL-1?), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1? axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1? signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1? antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1? signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1? ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-?B)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-?B and ultimately the depression of proinflammatory cytokine programs.ASC-mediated caspase-1/IL-1? signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1? signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.

Dataset Information

Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis.

Publications

Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis.

Similar Datasets

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