Article ; Online: Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops.
Annals of the rheumatic diseases
2019 Volume 78, Issue 6, Page(s) 787–795
Abstract: Objectives: The mechanisms driving onset of joint inflammation in arthritides such as rheumatoid arthritis and spondyloarthritis and the conversion to disease chronicity are poorly understood. We hypothesised mechanostrain could play an instrumental ... ...
| Abstract | Objectives: The mechanisms driving onset of joint inflammation in arthritides such as rheumatoid arthritis and spondyloarthritis and the conversion to disease chronicity are poorly understood. We hypothesised mechanostrain could play an instrumental role herein by engaging local and/or systemic pathways, thereby attenuating disease course and outcome. Methods: The development of collagen antibody-induced arthritis (CAIA) in C57BL/6 mice was evaluated both clinically and histologically under different loading regimens: control, voluntary running or hindpaw unloading. Bone surface porosity was quantified by high-resolution µ-CT. Gene expression analyses were conducted by microarrays and qPCR on microdissected entheses, murine and human synovial tissues (both normal and inflamed). Serum cytokines and chemokines were measured by ELISA. The influence of complement activation and T regulatory (Treg) cell function on the induction and resolution phase of disease was studied by respectively pharmacological modulation and conditional Treg depletion. Results: Voluntary running strongly impacts the course of arthritis by impairing the resolution phase of CAIA, leading to more persistent inflammation and bone surface porosity. Mechanical strain induced local complement activation, increased danger-associated molecular pattern expression, activating Fcγ receptors as well as changes in fibroblast phenotype. Interestingly, complement C5a receptor blockade inhibited the enhanced joint pathology caused by voluntary running. Moreover, Treg depletion led to a loss of disease resolution in CAIA mice, which was not observed under voluntary running conditions. Conclusions: Running promotes onset and chronicity of arthritis by local upregulation of complement activators and hampering regulatory T cell feedback loops. |
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| MeSH term(s) | Adult ; Aged ; Animals ; Arthritis, Experimental/immunology ; Arthritis, Experimental/physiopathology ; Arthritis, Rheumatoid/immunology ; Arthritis, Rheumatoid/physiopathology ; Chronic Disease ; Complement Activation/physiology ; Disease Progression ; Female ; Gene Expression Regulation/physiology ; Humans ; Male ; Mechanotransduction, Cellular/immunology ; Mice, Inbred C57BL ; Middle Aged ; Properdin/biosynthesis ; Running/physiology ; Stress, Mechanical ; Synovial Membrane/metabolism ; T-Lymphocytes, Regulatory/immunology |
| Chemical Substances | Properdin (11016-39-0) |
| Language | English |
| Publishing date | 2019-03-30 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 7090-7 |
| ISSN | 1468-2060 ; 0003-4967 |
| ISSN (online) | 1468-2060 |
| ISSN | 0003-4967 |
| DOI | 10.1136/annrheumdis-2018-214627 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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