Letter | Published:

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

Nature volume 498, pages 224227 (13 June 2013) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu. Rev. Immunol. 25, 473–523 (2007)

  2. 2.

    et al. Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans. Am. J. Pathol. 178, 1701–1714 (2011)

  3. 3.

    et al. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc. Natl Acad. Sci. USA 105, 15028–15033 (2008)

  4. 4.

    & Identification of polymorphisms in the human SHP1 gene. J. Hum. Genet. 47, 445–447 (2002)

  5. 5.

    et al. SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Lab. Invest. 88, 243–255 (2008)

  6. 6.

    & Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J. Hered. 66, 250–258 (1975)

  7. 7.

    , , , & “Viable motheaten,” a new allele at the motheaten locus. I. Pathology. Am. J. Pathol. 116, 179–192 (1984)

  8. 8.

    et al. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454 (1993)

  9. 9.

    , , & Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124–129 (1993)

  10. 10.

    SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009)

  11. 11.

    , & Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov. Med. 12, 65–74 (2011)

  12. 12.

    & NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nature Rev. Immunol. 10, 210–215 (2010)

  13. 13.

    et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007)

  14. 14.

    et al. Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl Acad. Sci. USA 107, 2574–2579 (2010)

  15. 15.

    et al. IL-1α and IL-1β recruit different myeloid cells and promote different stages of sterile inflammation. J. Immunol. 187, 4835–4843 (2011)

  16. 16.

    , & Commensal flora and the regulation of inflammatory and autoimmune responses. Semin. Immunol. 23, 139–145 (2011)

  17. 17.

    et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012)

  18. 18.

    & Sterile inflammation in the liver. Gastroenterology 143, 1158–1172 (2012)

  19. 19.

    & Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010)

  20. 20.

    , , & The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci. Signal. 3, re4 (2010)

  21. 21.

    et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998)

  22. 22.

    et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012)

  23. 23.

    , , , & Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30, 459–489 (2012)

  24. 24.

    et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006)

  25. 25.

    et al. Mice deficient in IL-1β manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183, 1427–1436 (1996)

  26. 26.

    , , , & Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol. 18, 399–407 (2006)

  27. 27.

    , & Kinase RIP3 is dispensable for normal NF-κBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 24, 1464–1469 (2004)

Download references

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.

Author information

Author notes

    • Mohamed Lamkanfi
    •  & Thirumala-Devi Kanneganti

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • John R. Lukens
    • , Gordon R. Johnson
    •  & Thirumala-Devi Kanneganti
  2. Animal Resources Center and the Veterinary Pathology Core, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Peter Vogel
  3. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Michelle A. Kelliher
  4. Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Yoichiro Iwakura
  5. Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium

    • Mohamed Lamkanfi
  6. Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium

    • Mohamed Lamkanfi

Authors

  1. Search for John R. Lukens in:

  2. Search for Peter Vogel in:

  3. Search for Gordon R. Johnson in:

  4. Search for Michelle A. Kelliher in:

  5. Search for Yoichiro Iwakura in:

  6. Search for Mohamed Lamkanfi in:

  7. Search for Thirumala-Devi Kanneganti in:

Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thirumala-Devi Kanneganti.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-19.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature12174

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.