Functional redundancy of MyD88-dependent signaling pathways in a murine model of histidyl-transfer RNA synthetase-induced myositis

Irina Fernandez, Lisa Harlow, Yunjuan Zang, Ru Liu-Bryan, William M. Ridgway, Paula R. Clemens, Dana P. Ascherman

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14 Scopus citations

Abstract

We have previously shown that i.m. administration of bacterially expressed murine histidyl-tRNA synthetase (HRS) triggers florid muscle inflammation (relative to appropriate control proteins) in various congenic strains of mice. Because severe disease develops even in the absence of adaptive immune responses to HRS, we sought to identify innate immune signaling components contributing to our model of HRS-induced myositis. In vitro stimulation assays demonstrated HRS-mediated activation of HEK293 cells transfected with either TLR2 or TLR4, revealing an excitatory capacity exceeding that of other bacterially expressed fusion proteins. Corresponding to this apparent functional redundancy of TLR signaling pathways, HRS immunization of B6.TLR2-/- and B6.TLR4 -/- single-knockout mice yielded significant lymphocytic infiltration of muscle tissue comparable to that produced in C57BL/6 wild-type mice. In contrast, concomitant elimination of TLR2 and TLR4 signaling in B6.TLR2 -/-.TLR4-/- doubleknockout mice markedly reduced the severity of HRS-induced muscle inflammation. Complementary subfragment analysis demonstrated that aa 60-90 of HRS were absolutely required for in vitro as well as in vivo signaling via these MyD88-dependent TLR pathways-effects mediated, in part, through preferential binding of exogenous ligands capable of activating specific TLRs. Collectively, these experiments indicate that multiple MyD88-dependent signaling cascades contribute to this model of HRSinduced myositis, underscoring the antigenic versatility of HRS and confirming the importance of innate immunity in this system.

Original languageEnglish (US)
Pages (from-to)1865-1872
Number of pages8
JournalJournal of Immunology
Volume191
Issue number4
DOIs
StatePublished - Aug 15 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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