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 defined1. 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 syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation2,3. Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1α production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6spin 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 Ptpn6spin mice. Notably, pharmacological and genetic blockade of the kinase RIP1 protected against wound-induced inflammation and tissue damage in Ptpn6spin 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 Ptpn6spin 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.
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Acknowledgements
We thank B. A. Buetler, V. M. Dixit and D. R. Green for supply of mutant mice. We thank R. Weinlich for helpful discussions. We thank M. Johnson in the St Jude Small Animal Imaging Center for helping to evaluate embryonic development in fetal liver transplantation studies. M.L. is supported by European Union Marie-Curie grant 256432, ERC grant 281600, and grants G030212N, 1.2.201.10.N.00 and 1.5.122.11.N.00 from the Fund for Scientific Research-Flanders. This work was supported by grants from the National Institutes of Health (grants AR056296, CA163507 and AI101935) and the American Lebanese Syrian Associated Charities (ALSAC) to T.-D.K.
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J.R.L., M.L. and T.-D.K. designed the study; J.R.L. performed experiments and G.R.J. provided technical assistance; J.R.L., M.L. and T.-D.K. analysed data and wrote the manuscript; M.A.K. and Y.I. provided genetic tools; P.V. performed and analysed the histopathology data; T.-D.K. oversaw the project.
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Lukens, J., Vogel, P., Johnson, G. et al. RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3. Nature 498, 224–227 (2013). https://doi.org/10.1038/nature12174
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DOI: https://doi.org/10.1038/nature12174
