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TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
Deepika Sharma, … , Peter Vogel, Thirumala-Devi Kanneganti
Deepika Sharma, … , Peter Vogel, Thirumala-Devi Kanneganti
Published November 19, 2018
Citation Information: J Clin Invest. 2019;129(1):150-162. https://doi.org/10.1172/JCI121372.
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Research Article Immunology Inflammation Article has an altmetric score of 8

TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

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Abstract

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.

Authors

Deepika Sharma, Ankit Malik, Clifford Guy, Peter Vogel, Thirumala-Devi Kanneganti

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Figure 2

Pyrin activation observed in MefvV726A/V726A monocytes is promoted by TNF signaling.

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Pyrin activation observed in MefvV726A/V726A monocytes is promoted by TN...
Pyrin expression in (A) BMDMs and (C) peritoneal cells following TLR and cytokine stimuli (TNF, IFN-β) over 24 hours. (B) Tnf expression in WT BMDMs stimulated with IFN-β. (D and F) Caspase-1 processing, pyrin expression, and (E and G) IL-1β release in monocytes in response to LPS (200 ng/ml) stimuli for 24 hours. (B, E, G) Data are presented as mean ± SEM and are representative of at least 3 independent repeats. ****P < 0.0001 compared with MefvV726A/V726A, 1-way ANOVA followed by Fischer’s LSD test.

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