Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger.
Document Type
Article
Publication Date
2008
Keywords
Animals, Autoimmune-Diseases, Autoimmunity, Ethylnitrosourea, Homozygote, Inflammation, Interleukin-1, Interleukin-1-Receptor-Associated-Kinases, Listeria-Infections, Mice-Mutant-Strains, Mutagenesis, Mutation, Myeloid-Differentiation-Factor-88, Protein-Tyrosine-Phosphatase-Non-Receptor-Type-6, Receptors-Interleukin-1, Toll-Like-Receptors
First Page
15028
Last Page
15033
JAX Source
Proc Natl Acad Sci U S A 2008 Sep; 105(39):15028-33.
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.
Recommended Citation
Croker BA,
Lawson BR,
Berger M,
Eidenschenk C,
Blasius AL,
Moresco EM,
Sovath S,
Cengia L,
Shultz LD,
Theofilopoulos AN,
Pettersson S,
Beutler BA.
Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc Natl Acad Sci U S A 2008 Sep; 105(39):15028-33.