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

Abstract

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 Myd88 poc , Irak4 otiose , and Il1r1 -null mutations, but not Ticam1 Lps2 , Stat1 m1Btlr , 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.

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Affiliated Institutions

• Imperial College London GB
• Scripps Research Institute US
• Jackson Laboratory US
• Walter and Eliza Hall Institute of Medical Research AU
• Karolinska Institutet SE

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