DBA/1 strain mice have been widely used for CIA studies, including the studies involved in the assessment of potential arthritis therapies (Malfait et al., 2001
). Usually, the DBA/1 strain mice show well induced CIA compared to that of the C57BL/6 mice. Though this study was performed with the C57BL/6 strain, the obese CIA mice well manifested arthritis. It suggested that obesity was related to overcome the resistance to develop CIA in C57BL/6 strain and to be susceptible to inflammation and autoimmunity. Obese CIA model in C57BL/6 strain itself was good evidence that obesity influence on developing autoimmune reaction. Diet-induced obesity (DIO) with C57BL/6 strain induced a good osteoarthritis model expressing high leptin, adiponectin, and IL-1α. DIO showed biochemical, neurobehavioral, musculoskeletal, inflammatory and structural knee joints change (Griffin et al., 2010
). This model exhibits that obesity has possibility to accelerate inflammation process through inflammatory adipokines and cytokines.
The C57BL/6 mice were fed a 60 Kcal high fat diet from the age of 4 weeks and they were immunized twice with CII. After immunization with CII, the obese CIA mice (C57BL/6 strain) showed a higher arthritis index score and histology score, and there was a more increased incidence of developing arthritis than that of the control (the C57BL/6 strain lean CIA mice) (). This result is important evidence that obesity has an amplifying action in the development of inflammatory arthritis.
The purified splenic lymphocytes from obese CIA mice or lean CIA mice, 10 weeks after the first immunization with CII, were or were not stimulated with anti-CD3. In both conditions (with or without anti-CD3 treatment), the mixed lymphocyte reaction (MLR) of the obese CIA mice was more increased than that of the lean CIA mice (). It is well known that T cells have a critical role in developing CIA. In the condition of the treatment with CII, CII specific response was shown in MLR. The splenocytes were proliferated in response to CII antigen. This result represents that obesity operates immune systems through activation of CII specific T cells. Fat cells secret some materials and these react with the immune system and particularly T cells.
Anti-CII IgG and anti-CII IgG2a (autoantibodies of CIA mice) were checked in the serum of both the obese and lean CIA mice. The levels of autoantibody of the obese CIA mice were higher than those of the lean CIA mice (). IgG2a type antibodies were produced by the Th1 response. Thus, obesity may cause the T cells of the CIA mice to differentiate toward Th1 cells.
Some investigators have demonstrated that obesity selectively promotes an expansion of the Th17 T cell sublineage, which is a subset with prominent pro-inflammatory roles in experimentally induced encephalomyelitis (EAE) model (Winer et al., 2009
). The T cells from DIO mice expand the Th17 cell pool and produce progressively more IL-17 than that of the lean mice (Winer et al., 2009
). Moreover, IL-17 plays an important role in the pathogenesis of RA and CIA. The studies that have employed strategies to neutralize or delete IL-17 have shown that Th17 cells have a pathogenic role in CIA (Nakae et al., 2003
; Lubberts et al., 2004
; Ju et al., 2008
; Sumarac-Dumanovic et al., 2009
). Both obesity and CIA activate Th17 cells and this produces IL-17. As expected, we observed a more increased number of Th17 cells in the obese CIA mice than that in the lean CIA mice. There was a higher IL-17 mRNA expression in the splenocytes of the obese CIA mice than that of the lean CIA mice (). Moreover, in immunohistochemistry, there was high expression in synovium of obese CIA compared with lean CIA mice (). We suggest obesity amplifies the joint inflammation of CIA mice through Th17 T cell differentiation and IL-17 production in joint synovium.
It is well established that obesity promotes Th1 deviation and induces inflammatory condition. However, it is not certain that Th17 cell is related with obese-induced inflammation and autoimmunity. Although the precise mechanisms are not clear, EAE model suggested Th17 cells and IL-17 in obese mice have an important role aggravating disease (Winer et al., 2009
). According to our results, obese CIA mice show more severe arthritis and an increased incidence of arthritis than do lean CIA mice. This is probably due to Th1 and Th17 differentiation. Sarkar et al. proposed that the Th1/Th2/Th17 balance is important to initiate autoimmunity (Sarkar et al., 2009
). Both CIA mice and DIO mice are biased towards Th1 and Th17 differentiation. It is no wonder that the obese CIA mice deviate more to Th1 and Th17 T cells than do the lean CIA mice. We suggest a hypothesis that Th17 cells may be influenced by adipokines and Th17 cells may have some adipokine receptors on cell surface. Clarifying these mechanisms of relationship between adipokines and Th17 cells or IL-17 would be another study.
We made an animal model that represented RA with obesity. In the future, we will investigate the interactions between several cytokines and adipokines using this obese CIA model. Obesity studies have revealed that adipokines are important factors in inflammation. The upregulated resistin at local sites of inflammation and the link between serum resistin, inflammation and the disease activity score suggest a role for resistin in the pathogenesis of RA (Senolt et al., 2007
). Bokarewa et al. demonstrated that resistin is a molecule that is accumulated at the site of inflammation and that recombinant resistin injected intraarticularly caused a dose-dependent increase of arthritis (Bokarewa et al., 2005
). Neutralization of resistin will be an important therapeutic target in the future. Visfatin, which is also known as pre-B cell colony-enhancing factor, is also another candidate for inducing inflammation in RA. The visfatin gene expression in the synovial tissue and PBMCs of RA patients was significantly higher than that of the controls (Matsui et al., 2008
). The positive correlation between the levels of visfatin and resistin suggests that visfatin plays a role in the inflammation of RA (Straburzyńska-Lupa et al., 2010
). In the future, we will test the adipokines in obese CIA mice and try to find therapeutic modalities through blocking the inflammatory adipokines (Seo et al., 2011
Other investigators have created adjuvant-induced arthritis (AIA) in obese rats. They tested the effect of the cannabinoid CB1 receptor antagonist rimonbant on AIA in obese rats. They also showed that the inflammation reaction in obese rats is more severe than that in lean rats. The same as in obese AIA rats, it is possible to conduct several therapeutic trials using obese CIA mice (Croci et al., 2007
In conclusion, obesity plays an addictive role in the inflammation of an inflammatory arthritis model through CII specific T cell differentiation -Th17 T cells differentiation. IL-17 is a pivotal cytokine to accelerate joints inflammation in obesity. The obese CIA model has value that we can control and investigate the obese condition in an inflammatory arthritis model and we were able to pinpoint several therapeutic target molecules.