Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 5, Pages 1783-1800Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83669
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Funding
- Fonds zur Forderung des akademischen Nachwuchses of the Zurcher Universitatsverein
- Swiss Philanthropy Foundation
- University of Zurich
- Swiss National Science Foundation [314730146204, CRSII3_154488/1, 310030-120312, 320000-114009/3, 32473B_135694/1]
- Swiss IBD Cohort [3347CO-108792]
- Zurich Center for Integrative Human Physiology of the University of Zurich
- Novartis Foundation for Biomedical Research
- Hartmann-Muller Foundation
- Abbvie IBD Awar
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Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1 beta, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1 beta secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1 beta release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1 beta. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1 beta levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
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