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- W4313366080 abstract "Abstract Neutrophilic dermatoses are a group of inflammatory skin disorders characterized by sterile infiltrates of neutrophils. These syndromes include pyoderma gangrenosum (PG) and Sweet’s syndrome (SS), and they are associated with an increased incidence of inflammatory bowel disease, rheumatoid arthritis, and acute myeloid leukemia. IL-1β is detectable in skin lesions, and IL-1 neutralizing therapies have met with success in some patients. Splicing variants and promoter region deletions of protein tyrosine phosphatase-6 (PTPN6) are a feature of SS and PG. Mice lacking Ptpn6 develop a cutaneous inflammatory disease that is dependent on the IL-1 receptor, G-CSF, and neutrophils, but the source of IL-1 and the mechanisms of IL-1 release remain unclear. Here, we investigated the mechanisms controlling IL-1α/β release specifically from neutrophils (Ptpn6ΔPMN) by inhibiting Caspase-8-dependent apoptosis and Ripk1/Ripk3/Mlkl-regulated necroptosis. Loss of Ripk1 from neutrophils accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6ΔPMN mice. Ptpn6ΔPMN neutrophils displayed increased p38-dependent Ripk1-independent IL-1 and TNF production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 MAP kinase activation to control TNF and IL-1α/β transcription, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β release. These findings implicate neutrophils as the dominant producers of IL-1 in neutrophilic dermatoses, and identify novel therapeutic targets for the treatment of these skin disorders." @default.
- W4313366080 created "2023-01-06" @default.
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- W4313366080 date "2019-05-01" @default.
- W4313366080 modified "2023-10-01" @default.
- W4313366080 title "Ptpn6 inhibits Caspase-8- and Ripk3/Mlkl-dependent inflammation" @default.
- W4313366080 doi "https://doi.org/10.4049/jimmunol.202.supp.59.4" @default.
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