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.

LST1/A Is a Myeloid Leukocyte-specific Transmembrane Adaptor Protein Recruiting Protein Tyrosine Phosphatases SHP-1 and SHP-2 to the Plasma Membrane

“…Motheaten, viable motheaten, and spin mouse strains bearing loss of function mutations in the SHP-1 encoding gene (34,35) exhibit granulocyte and macrophage hyper-responsiveness to cytokines (36) and development of severe autoinflammatory disease (35,37). Moreover, partial SHP-1 deficiency leads to severe autoimmune disease, which develops even in the absence of B-and T-lymphocytes but is dependent on signaling via innate immune receptors, such as IL-1 and Toll-like receptors (35,37). Most likely, cells of the myeloid lineage induce the chronic inflammation observed in SHP-1 insufficient animals.…”

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

“…Consistent with our initial experiments with NFκB, treatment with ISO also resulted in the down-regulation of ATF-2, Il1r1 and Tnfrsf1b, along with the modest up-regulation of Ripk2. ATF-2, which is known to interact with c-jun, is a transcription factor primarily regulated by the stress activated MAPKs JNK and p38 and is known to play a role in the hypertrophic response [19], while Il1r1 is mainly involved in the immune and inflammatory response, through its interaction with Myd88, although it also plays a role in the activation of NFκB [20]. Tnfrsf1b plays a role in the activation of NFκB, but only in the absence of Rip proteins like Ripk2 [21].…”

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

“…Moreover, at this stage hyperinsulinemic larvae appeared to be immunosuppressed at the transcriptional level, whereas the only immune modulator showing an increased expression was ptpn6. In mammals and zebrafish, ptpn6 has been reported to be a negative regulator of the immune response (Zhang et al 2000, Tsui et al 2006, Pao et al 2007, Croker et al 2008, Lorenz 2009, Kanwal et al 2013) and a key determinant of development of insulin resistance and nonalcoholic fatty liver diseases (Xu et al 2012(Xu et al , 2014a. We found that knocking down of ptpn6 interfered with the inhibitory effect observed on key transcription factors and signal mediators of the NF-kB pathway as well as on various cytokines in larvae that had received injections of insulin.…”

“…This gene is a well-known immune modulator playing a critical role as a negative regulator of the immune response , Croker et al 2008. Importantly, PTPN6 has been described as a modulator of insulin signaling (Dubois et al 2006), and recent findings have demonstrated its importance in the development of insulin resistance and non-alcoholic fatty liver diseases in diet-induced obesity (Xu et al 2014a,b).…”

“…PTPN6 (also known as SHP1) is expressed mainly in hematopoietic cells (Yi et al 1992) and has been described as an important negative regulator of immune signaling pathways , Croker et al 2008. In addition, it has been reported that PTPN6 may be involved in the development of insulin resistance and non-alcoholic fatty liver diseases in obesity (Xu et al 2012(Xu et al , 2014a.…”