The idiopathic inflammatory myopathies (IIMs) represent a group of systemic autoimmune disorders in which muscle and extra-muscular organs are targeted for immune-mediated destruction. We have previously established a model of histidyl-tRNA synthetase (HRS)-induced myositis that involves MyD88-dependent innate immune signaling pathways featuring Toll-like receptors 2 and 4 (TLR2, TLR4). Given the prominent role of these TLRs in our model of HRS-induced myositis, we hypothesize that heightened activation of the downstream transcription regulator NF-?B is ultimately responsible for various inflammatory cascades as well as non-immune pathways promoting muscle dysfunction in this system?effectively linking HRS-induced myositis/IIM with other disorders (including muscular dystrophy as well as sepsis- and trauma/ischemia- induced myopathies) in which NF-?B dysregulation contributes to muscle inflammation, muscle degeneration, and impaired regenerative potential. Through a series of in vitro culture systems and in vivo immunization strategies involving knockout mice lacking critical components of MyD88-dependent signaling pathways, we will systematically examine the impact of HRS-induced TLR signaling and NF-?B activation on T cell migration, T cell activation, and muscle weakness.
While Specific Aim 1 will focus on HRS-induced changes in T cell function and TLR-mediated activation of vascular endothelium (leading to lymphocytic infiltration of target organs), Specific Aim 2 will define direct and indirect pathways of HRS-induced NF-?B activation in muscle tissue through in vitro myoblast stimulation assays as well as additional immunization studies focusing on correlations between muscle inflammation, NF-?B activation, and in vivo/ex vivo parameters of muscle weakness. Complementary in vivo assessment tools including MRI and the use of NF-?B-luciferase transgenic mice will further define the relationship between HRS-mediated NF-?B activation and muscle dysfunction, providing the foundation for experimental trials of comparative NF-?B inhibition in Specific Aim 3. Collectively, these studies will elucidate the contribution of innate immunity to the pathogenesis of IIM, supplementing more traditional paradigms of antigen-specific, adaptive immune recognition and identifying therapeutic targets that are potentially relevant to a range of human inflammatory muscle diseases.

Public Health Relevance

Over the last 10 years, we have established two independent models of autoimmune muscle disease that feature different relative contributions from innate and adaptive immune responses to histidyl-tRNA synthetase (HRS), the most common antigen/protein target in human disease. Intriguingly, the ability of recombinant HRS to activate Toll-like receptors (TLRs) and associated MyD88-dependent signaling cascades suggests that our models of HRS-induced myositis may provide a more general framework for understanding subtypes of muscular dystrophy as well as other inflammatory muscle diseases involving downstream activation of the key transcription factor NF-?B (including those disorders associated with sepsis, trauma, and/or ischemia). Therefore, as a prelude to the development of novel therapeutic agents for autoimmune as well as non-autoimmune muscle inflammation, this proposal will define the relationship between immune dysregulation, aberrant NF-?B-mediated molecular signaling cascades, and muscle dysfunction in HRS-induced myositis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR071369-01
Application #
9286500
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
2017-04-10
Project End
2022-03-31
Budget Start
2017-04-10
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$380,027
Indirect Cost
$106,283
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Sciorati, Clara; Monno, Antonella; Doglio, Maria Giulia et al. (2018) Exacerbation of Murine Experimental Autoimmune Myositis by Toll-Like Receptor 7/8. Arthritis Rheumatol 70:1276-1287
Ascherman, D P; Zang, Y; Fernandez, I et al. (2018) An Autoimmune Basis for Raynaud's Phenomenon: Murine Model and Human Disease. Arthritis Rheumatol 70:1489-1499