Persistent IL-6 expression is induced in the olfactory bulb of arthritis model mice before the onset of arthritis

Abstract

Abstract Background Rheumatoid arthritis (RA) is complicated by psychiatric symptoms. There are many reports of abnormalities in the brains of RA patients and models of arthritis. However, it is unclear when these abnormalities appear and where they are distributed. In this study, we analyzed the spatiotemporal gene expression changes in the brains of mice with collagen-induced arthritis. Methods Mice were divided into three groups: i) collagen-induced arthritis (all mice developed arthritis on day 35): complete Freund’s adjuvant (CFA) and type II collagen at initial immunization, and incomplete Freund’s adjuvant (IFA) and type II collagen at booster immunization; ii) C(+/-) (50% mice developed arthritis on day 35): only IFA at booster immunization; and iii) C(-/-) (no arthritis): only CFA at initial immunization and only IFA at booster immunization. Whole brains were collected at 10 stages of arthritis and divided into six sections. RT-PCR was performed using RNA extracted from the divided brains, and the expressions of proinflammatory cytokines and glial markers were semi-quantified. At the same time, the arthritis score, body weight, and food and water intake were recorded and analyzed for correlation with brain gene expression. Results After booster immunization, a transient increase in ITGAM and IL-1β was observed in multiple areas. Interestingly, IL-6 was persistently expressed before the onset of arthritis in the olfactory bulb (OB), which correlated with body weight loss and decreased food intake. This characteristic change in the OB was similarly observed in the C(+/-), but not in the C(-/-). Furthermore, in the C(+/-), non-arthritis mice showed the same changes in the OB as the arthritis mice. This elevation of IL-6 persisted throughout the chronic phase to day 84. Conclusion Persistent elevation of IL-6 in the OB from the early stage of arthritis may be an important finding that might explain the neuropsychiatric pathophysiology of RA, which is present in the early stages of disease, and presents as a variety of symptoms over time. These findings also support the idea that the OB may be affected in early disease and persistently under particular peripheral immunoinflammatory conditions, as has been reported in a variety of neurodegenerative diseases.