Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Ben A. Croker, Brian R. Lawson, Michael Berger, Celine Eidenschenk, Amanda L. Blasius, Eva Marie Y. Moresco, Sosathya Sovath, Louise Cengia, Leonard D. Shultz, Argyrios N. Theofilopoulos, Sven Pettersson, Bruce Alan Beutler

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


A recessive phenotype called spin (spontaneous inflammation) was induced by N-ethyl-N-nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, and antichromatin antibodies. They are immunocompetent and show enhanced resistance to infection by Listeria monocytogenes. TLR-induced TNF and IL-1 production are normal in macrophages derived from spin mice. The autoinflammatory phenotype of spin mice is fully suppressed by compound homozygosity for Myd88poc, Irak4otiose, and Il1r1-null mutations, but not Ticam1Lps2, Stat1m1Btlr, or Tnf-null mutations. Both autoimmune and autoinflammatory phenotypes are suppressed when spin homozygotes are derived into a germ-free environment. The spin phenotype was ascribed to a viable hypomorphic allele of Ptpn6, which encodes the tyrosine phosphatase SHP1, mutated in mice with the classical motheaten alleles me and me-v. Inflammation and autoimmunity caused by SHP1 deficiency are thus conditional. The SHP1-deficient phenotype is driven by microbes, which activate TLR signaling pathways to elicit IL-1 production. IL-1 signaling via MyD88 elicits inflammatory disease.

Original languageAmerican English
Pages (from-to)15028-15033
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - 30 Sep 2008
Externally publishedYes


  • Ptpn6
  • Toll-like receptors


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