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

(2013) NATURE. 498(7453). p.224-U122
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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(1). 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(2,3). Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1 alpha production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6(spin) mice, whereas inflammasome signalling and IL-1 beta-mediated events are dispensable. IL-1 alpha 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-kappa B 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-1 alpha production, whereas inflammasome signalling and RIP3-mediated necroptosis are dispensable. Thus, we have unravelled a novel inflammatory circuit in which RIP1-mediated IL-1 alpha secretion in response to deregulated SHP-1 activity triggers an inflammatory destructive disease that proceeds independently of inflammasomes and programmed necrosis. Accession Number: WOS:000320283400047
Keywords
IDENTIFICATION, AUTOIMMUNITY, PHOSPHATASES, MICE, DISEASE, ACTIVATION, GENE, CELL, MOTH-EATEN, STERILE INFLAMMATION

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MLA
Lukens, John R, Peter Vogel, Gordon R Johnson, et al. “RIP1-driven Autoinflammation Targets IL-1 Alpha Independently of Inflammasomes and RIP3.” NATURE 498.7453 (2013): 224–U122. Print.
APA
Lukens, J. R., Vogel, P., Johnson, G. R., Kelliher, M. A., Iwakura, Y., Lamkanfi, M., & Kanneganti, T.-D. (2013). RIP1-driven autoinflammation targets IL-1 alpha independently of inflammasomes and RIP3. NATURE, 498(7453), 224–U122.
Chicago author-date
Lukens, John R, Peter Vogel, Gordon R Johnson, Michelle A Kelliher, Yoichiro Iwakura, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti. 2013. “RIP1-driven Autoinflammation Targets IL-1 Alpha Independently of Inflammasomes and RIP3.” Nature 498 (7453): 224–U122.
Chicago author-date (all authors)
Lukens, John R, Peter Vogel, Gordon R Johnson, Michelle A Kelliher, Yoichiro Iwakura, Mohamed Lamkanfi, and Thirumala-Devi Kanneganti. 2013. “RIP1-driven Autoinflammation Targets IL-1 Alpha Independently of Inflammasomes and RIP3.” Nature 498 (7453): 224–U122.
Vancouver
1.
Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M, et al. RIP1-driven autoinflammation targets IL-1 alpha independently of inflammasomes and RIP3. NATURE. 2013;498(7453):224–U122.
IEEE
[1]
J. R. Lukens et al., “RIP1-driven autoinflammation targets IL-1 alpha independently of inflammasomes and RIP3,” NATURE, vol. 498, no. 7453, pp. 224-U122, 2013.
@article{4100964,
  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(1). 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(2,3). Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1 alpha production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6(spin) mice, whereas inflammasome signalling and IL-1 beta-mediated events are dispensable. IL-1 alpha 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-kappa B 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-1 alpha production, whereas inflammasome signalling and RIP3-mediated necroptosis are dispensable. Thus, we have unravelled a novel inflammatory circuit in which RIP1-mediated IL-1 alpha secretion in response to deregulated SHP-1 activity triggers an inflammatory destructive disease that proceeds independently of inflammasomes and programmed necrosis.  
Accession Number: WOS:000320283400047},
  author       = {Lukens, John R and Vogel, Peter and Johnson, Gordon R and Kelliher, Michelle A and Iwakura, Yoichiro and Lamkanfi, Mohamed and Kanneganti, Thirumala-Devi},
  issn         = {0028-0836},
  journal      = {NATURE},
  keywords     = {IDENTIFICATION,AUTOIMMUNITY,PHOSPHATASES,MICE,DISEASE,ACTIVATION,GENE,CELL,MOTH-EATEN,STERILE INFLAMMATION},
  language     = {eng},
  number       = {7453},
  pages        = {224--U122},
  title        = {RIP1-driven autoinflammation targets IL-1 alpha independently of inflammasomes and RIP3},
  url          = {http://dx.doi.org/10.1038/nature12174},
  volume       = {498},
  year         = {2013},
}

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