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

Abstract

ObjectivesThe 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.MethodsThe 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.ResultsVoluntary 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.ConclusionsRunning promotes onset and chronicity of arthritis by local upregulation of complement activators and hampering regulatory T cell feedback loops.

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

“…The molecular results of the PE effect are not easily comparable with previous studies due to the low number of reports, which had objectives aimed at particular aspects of the disease. However, we can distinguish that the negative effect of PE has also been reported in the two most recent and complete studies in this field [16,17]. The results of these studies suggest a direct link between the degree of mechanical stress to inflammation and tissue localization, which strengthens previous studies that propose biomechanical factors as potential determinants for the topographic pattern of joint disorders in arthritis [46].…”

“…Consistent with the genetic analysis, our histological findings showed that PE had an adverse effect on increasing the inflammatory infiltrate and the joint destruction. In experimental models of arthritis, it has been confirmed that mechanical stress increase joint inflammation, stimulate the progression and chronicity of arthritis and structural damage [16,17,48]; besides, the mechanical stress decrease the bone quality [16]. In contrast to our findings, other studies in the AIA model have shown an anti-inflammatory effect of PE in some parameters such as synovial hyperplasia [49,50], and joint destruction [51].…”

“…Cambré et al, suggest that the link between mechanical stress and the onset of arthritis is explained by local recruitment of Ly6high inflammatory cells elicited by mechanostress-induced chemokine induction in resident mesenchyme cells [17]. They also provide evidence of the local participation of the complement activators to maintain the progression and chronicity of arthritis through an impaired resolution [16].…”

“…Although the systemic benefits of PE in rheumatic patients are well recognized, the direct consequences of PE in active synovitis and the potential role of PE accelerating joint destruction are not clear. Some reports have shown that mechanical load influences the onset and worsens the progression of the disease in experimental animal models of arthritis [16,17]; therefore, the consequences of PE on inflamed joints remain a topic that should be addressed.…”

The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies

“…Considerable recent developments have occurred in experimental enthesitis research where high mechanical stressing at entheses is associated with local immune system activation 59 93 94. Non-SpA-related enthesitis can result from repeated mechanical strain in healthy individuals (eg, tennis elbow) and usually resolves spontaneously, whereas inflammation in SpA shows chronicity 59.…”