Abstract
Abstract Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated pivotal role for several kinases, such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP1 mediated inflammation, we undertook genetic approach and discovered Apoptosis signal-regulating kinases (ASK1 and ASK2) as novel kinases regulating the Ptpn6 mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin mediated disease by controlling pro-inflammatory signaling in the neutrophils. Collectively, this study identifies SHP1 and ASK signaling crosstalk as a critical regulator of IL-1α driven inflammation and open future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
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