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Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops

Isabelle Cambré (UGent) , Djoere Gaublomme (UGent) , Nadia Schryvers (UGent) , Stijn Lambrecht (UGent) , Rik Lories, Koen Venken (UGent) and Dirk Elewaut (UGent)
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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 mu-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 Fc gamma 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.
Keywords
RHEUMATOID-ARTHRITIS, JOINT, SPONDYLOARTHRITIS, ENTHESITIS, RECEPTORS, MICE, TNF, C3A

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MLA
Cambré, Isabelle et al. “Running Promotes Chronicity of Arthritis by Local Modulation of Complement Activators and Impairing T Regulatory Feedback Loops.” ANNALS OF THE RHEUMATIC DISEASES 78.6 (2019): 787–795. Print.
APA
Cambré, I., Gaublomme, D., Schryvers, N., Lambrecht, S., Lories, R., Venken, K., & Elewaut, D. (2019). Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops. ANNALS OF THE RHEUMATIC DISEASES, 78(6), 787–795.
Chicago author-date
Cambré, Isabelle, Djoere Gaublomme, Nadia Schryvers, Stijn Lambrecht, Rik Lories, Koen Venken, and Dirk Elewaut. 2019. “Running Promotes Chronicity of Arthritis by Local Modulation of Complement Activators and Impairing T Regulatory Feedback Loops.” Annals of the Rheumatic Diseases 78 (6): 787–795.
Chicago author-date (all authors)
Cambré, Isabelle, Djoere Gaublomme, Nadia Schryvers, Stijn Lambrecht, Rik Lories, Koen Venken, and Dirk Elewaut. 2019. “Running Promotes Chronicity of Arthritis by Local Modulation of Complement Activators and Impairing T Regulatory Feedback Loops.” Annals of the Rheumatic Diseases 78 (6): 787–795.
Vancouver
1.
Cambré I, Gaublomme D, Schryvers N, Lambrecht S, Lories R, Venken K, et al. Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops. ANNALS OF THE RHEUMATIC DISEASES. 2019;78(6):787–95.
IEEE
[1]
I. Cambré et al., “Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops,” ANNALS OF THE RHEUMATIC DISEASES, vol. 78, no. 6, pp. 787–795, 2019.
@article{8622893,
  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 mu-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 Fc gamma 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.},
  author       = {Cambré, Isabelle and Gaublomme, Djoere and Schryvers, Nadia and Lambrecht, Stijn and Lories, Rik and Venken, Koen and Elewaut, Dirk},
  issn         = {0003-4967},
  journal      = {ANNALS OF THE RHEUMATIC DISEASES},
  keywords     = {RHEUMATOID-ARTHRITIS,JOINT,SPONDYLOARTHRITIS,ENTHESITIS,RECEPTORS,MICE,TNF,C3A},
  language     = {eng},
  number       = {6},
  pages        = {787--795},
  title        = {Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2018-214627},
  volume       = {78},
  year         = {2019},
}

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