Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger.
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.
Croker
Ben A
BA
Department of Genetics, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Lawson
Brian R
BR
Rutschmann
Sophie
S
Berger
Michael
M
Eidenschenk
Celine
C
Blasius
Amanda L
AL
Moresco
Eva Marie Y
EM
Sovath
Sosathya
S
Cengia
Louise
L
Shultz
Leonard D
LD
Theofilopoulos
Argyrios N
AN
Pettersson
Sven
S
Beutler
Bruce Alan
BA
D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D015551:Autoimmunity / Q000235:genetics; D005038:Ethylnitrosourea / Q000494:pharmacology; D006720:Homozygote; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D008088:Listeriosis / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
D007375:Interleukin-1; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D005038:Ethylnitrosourea