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

被引:91
作者
Croker, Ben A. [1 ,3 ]
Lawson, Brian R. [2 ]
Rutschmann, Sophie [4 ]
Berger, Michael [1 ]
Eidenschenk, Celine [1 ]
Blasius, Amanda L. [1 ]
Moresco, Eva Marie Y. [1 ]
Sovath, Sosathya [1 ]
Cengia, Louise [3 ]
Shultz, Leonard D. [5 ]
Theofilopoulos, Argyrios N. [2 ]
Pettersson, Sven [6 ]
Beutler, Bruce Alan [1 ]
机构
[1] Scripps Res Inst, Dept Genet, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[3] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Canc & Haematol Div, Parkville, Vic 3050, Australia
[4] Univ London Imperial Coll Sci Technol & Med, Fac Med, London SW7 2AZ, England
[5] Jackson Lab, Bar Harbor, ME 04609 USA
[6] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
Ptpn6; Toll-like receptors;
D O I
10.1073/pnas.0806619105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:15028 / 15033
页数:6
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