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

doi:10.1073/pnas.0806619105

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

Departments of *Genetics and
^‡Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037;
^†Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia;
^§Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;
^¶The Jackson Laboratory, Bar Harbor, ME 04609; and
^‖Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Contributed by Bruce Alan Beutler, July 14, 2008 (received for review July 1, 2008)

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.

Footnotes

**To whom correspondence should be addressed. E-mail: bruce{at}scripps.edu
Author contributions: B.A.C. and B.A.B. designed research; B.A.C., B.R.L., S.R., M.B., C.E., A.L.B., S.S., L.C., and S.P. performed research; L.D.S. contributed new reagents/analytic tools; B.A.C., B.R.L., S.R., A.N.T., and B.A.B. analyzed data; and B.A.C., E.M.Y.M., and B.A.B. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0806619105/DCSupplemental.