Antigen‐Induced Arthritis Leads to Depression‐Like Behavior in Mice Mediated by Central TNFα

Rheumatoid arthritis (RA) is a relapsing inflammatory condition of the joints. There are many debilitating neurological and psychological manifestations associated with RA, including chronic pain, and depression. These symptoms contribute to a reduction of quality of life, particularly because they are often present when the peripheral disease is in remission. While progress has been made in the treatment of joint inflammation, mechanisms that underlie the central neural manifestations of RA have yet to be characterized and treatment options identified. Using a mouse model of RA, we sought to demonstrate depression‐like behaviour in the absence of joint inflammation and determine a mechanism for this condition. We hypothesized that inflammation would lead to depression‐like behaviour mediated by central cytokines. To test the hypothesis, we used the antigen‐induced arthritis (AIA) model in mice. C57Bl/6 male mice (8–10 wk) were sensitized with methylated bovine serum albumin (mBSA) 14 days prior to the immune challenge. Knee intra‐articular injection of mBSA was performed to induce joint inflammation. After 1 or 13 days, mice were subjected to the tail suspension test to evaluate the presence of depression‐like behavior and pain was assessed with a Von Frey apparatus. To evaluate the inflammatory state of the brain, multiplex cytokine analysis (32 cytokines) were performed in hippocampal specimens and microglial staining was performed using anti‐Iba‐1 antibodies. Anti‐TNFα injections were performed intracerebroventricularly (icv) to evaluate to role of this cytokine on behaviour. One day after immune challenge, joint inflammation was observed in the knee. After 13 days, no neutrophil infiltration was observed, suggesting a basal, non‐inflamed state. We observed high levels of pain on day 1, which persisted until day 13. Depression‐like behaviour was only seen on day 13, suggesting an alteration in behavior in the absence of knee inflammation. To validate this result, mice with AIA were treated with the antidepressant imipramine (30 mg/kg). We saw a reduction in the depression‐like behavior previously observed. Moreover, to rule out joint pain on the behavior reported, we treated AIA mice locally with the non‐opioid analgesic dipyrone. Reducing joint pain did not influence the depression‐like behavior. Microglia analysis on the hippocampus showed no overt activation of microglia at either time point. Cytokine analysis showed an increase in KC, MCP‐1, and TNFα (p=0.08) in the hippocampus of AIA mice after day 1, but no changes at day 13. In order to test if TNFα may be involved in the depression behaviour, we injected anti‐TNFα icv on day 0. At day 13, we observed a reduction of depression‐like behaviour in AIA mice, suggesting a role for TNFα on this outcome. We conclude that depression‐like behaviour in a mouse model of RA is mediated by central cytokines. The mechanism of how TNFα is modulating this behavior remains to be determined. Support or Funding Information This work was supported by Canadian Institutes of Health Research (CIHR) and National Counsel of Technological and Scientific Development (CNPq – Brazil). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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