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TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
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TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
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Journal Article
TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
2019
Overview
Pyrin is an inflammasome sensor that promotes caspase-1-mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (MefvV726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.
Publisher
American Society for Clinical Investigation
Subject
/ Ankle
/ Caspase
/ Colitis
/ Familial Mediterranean fever
/ Mice
/ Mutation
/ Prevalence studies (Epidemiology)
/ Proteins
/ Receptors, Tumor Necrosis Factor, Type I - genetics
/ Receptors, Tumor Necrosis Factor, Type I - immunology
/ Receptors, Tumor Necrosis Factor, Type II - genetics
/ Receptors, Tumor Necrosis Factor, Type II - immunology
/ Rodents
/ Roles
/ Signal Transduction - genetics
/ Signal Transduction - immunology
/ Tumor necrosis factor receptors
/ Tumor Necrosis Factor-alpha - genetics
