Exacerbation of Murine Experimental Autoimmune Myositis by Toll-Like Receptor 7/8

Clara Sciorati, Antonella Monno, Maria Giulia Doglio, Elena Rigamonti, Dana Ascherman, Angelo A. Manfredi, Patrizia Rovere-Querini

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objective: Toll-like receptor 7 (TLR-7), TLR-8, and interferon (IFN)–induced genes are expressed in patients with idiopathic inflammatory myositis. This study was undertaken to investigate whether their activation influences the natural history of the disease. Methods: Experimental autoimmune myositis was induced in mice by injection of the amino-terminal portion of the murine histidyl–transfer RNA synthetase (HisRS). Disease was compared in the presence or the absence of the TLR-7/8 agonist R-848 in wild-type mice and in mice that fail to express the IFNα/β receptor (IFNα/βR-null mice). Results: Experimental autoimmune myositis induced by a single intramuscular immunization with HisRS spontaneously abated after 7–8 weeks. In contrast, levels of anti-HisRS autoantibodies, endomysial/perimysial leukocyte infiltration, and myofiber regeneration persisted at the end of the follow-up period (22 weeks after immunization) in mice immunized with HisRS in the presence of R-848. Myofiber major histocompatibility complex (MHC) class I molecules were detectable only in mice immunized with both HisRS and R-848. MHC up-regulation occurred early and in muscles that were not directly injected with HisRS. Muscle MHC expression paralleled with leukocyte infiltration. MHC class I molecules were selectively up-regulated in myotubes challenged with R-848 in vitro. Type I IFN was necessary for the prolonged autoantibody response and for the spreading of the autoimmune response, as demonstrated using IFNα/βR-null mice. Muscle infiltration was maintained in the injected muscle up to the end of the follow-up period. Conclusion: TLR-7/8 activation is necessary to induce and maintain a systemic autoimmune response targeting the skeletal muscle. This experimental autoimmune myositis model reproduces many characteristics of human idiopathic inflammatory myopathies and may represent a tool for preclinical studies.

Original languageEnglish (US)
Pages (from-to)1276-1287
Number of pages12
JournalArthritis and Rheumatology
Volume70
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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