RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3

The protein-tyrosine phosphatase SHP-1 plays critical roles in immune signaling, but how mutations in SHP-1 cause inflammatory disease in humans remains poorly defined(1). Mice homozygous for the Y208N amino acid substitution in the carboxy-terminus of SHP-1 (referred to as Ptpn6(spin) mice) spontaneously develop a severe inflammatory syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation(2,3). Here, we report that RIP1-regulated IL-1α production by hematopoietic cells critically mediates chronic inflammatory disease in Ptpn6(spin) mice, whereas inflammasome signaling and IL-1β-mediated events were dispensable. IL-1α was also critical for exacerbated inflammatory responses and unremitting tissue damage upon footpad microabrasion of Ptpn6(spin) mice. Intriguingly, pharmacological and genetic blockade of the kinase RIP1 protected against wound-induced inflammation and tissue damage in Ptpn6(spin) mice, whereas RIP3 deletion failed to do so. Moreover, RIP1-mediated inflammatory cytokine production was attenuated by NF-κB and ERK inhibition. Together, our results suggest that wound-induced tissue damage and chronic inflammation in Ptpn6(spin) mice are critically dependent on RIP1-mediated IL-1α production, whereas inflammasome signaling and RIP3-mediated necroptosis were dispensable. Thus, we have unravelled a novel inflammatory circuit in which RIP1-mediated IL-1α secretion in response to deregulated SHP-1 activity triggers an inflammatory destructive disease that proceeds independently of inflammasomes and programmed necrosis.