English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

The protein-tyrosine phosphatase SHP-1 has critical roles in immune signalling, but how mutations in SHP-1 cause inflammatory disease in humans remains poorly defined. Mice homozygous for the Tyr208Asn 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. Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1α production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6(spin) mice, whereas inflammasome signalling and IL-1β-mediated events are dispensable. IL-1α was also crucial for exacerbated inflammatory responses and unremitting tissue damage upon footpad microabrasion of Ptpn6(spin) mice. Notably, 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 indicate that wound-induced tissue damage and chronic inflammation in Ptpn6(spin) mice are critically dependent on RIP1-mediated IL-1α production, whereas inflammasome signalling and RIP3-mediated necroptosis are 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.

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