Ptpn6 Inhibits IL-1 Release from Neutrophils By Regulation of Caspase-8- and Ripk3/Mlkl-Dependent Forms of Cell Death

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 risk of inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancy, particularly monocytic or myelomonocytic leukemia (AML). IL-1 was first proposed in 1987 as a factor in SS, and the presence of “fragmented neutrophil nuclei” was hypothesized to contribute to disease. IL-1 has subsequently been reported at high levels in lesions of SS, and IL-1 neutralizing therapies have met with success in some SS patients. PG is also reported to be responsive to IL-1 neutralizing therapy, including PG patients with psoriatic arthritis. Splicing variants and promoter region deletions of protein tyrosine phosphatase-6 (PTPN6, or Src homology region 2 domain-containing phosphatase-1, SHP1) are a feature of SS and PG, consistent with the findings that mutations in Ptpn6 drive spontaneous IL-1R-dependent skin inflammation in mice. Mice lacking Ptpn6 develop a cutaneous inflammatory disease that is dependent on the IL-1 receptor (IL-1R), G-CSF, and neutrophils. We hypothesized that production of IL-1 by dying neutrophils drives skin inflammation in the setting of Ptpn6 deficiency.