title: RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3.
abstract: 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.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Johnson
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D016923:Cell Death; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005121:Extremities / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing; D014947:Wounds and Injuries / Q000276:immunology / Q000473:pathology
chemical_list: D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016328:NF-kappa B; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse