Olfactory Bulbs in Arthritis Model Mouse Persistently Express Interleukin-6 before the Onset of Arthritis: Relationship to Food Intake.

INTRODUCTION: Rheumatoid arthritis (RA) can be comorbid with psychiatric symptoms. Brain abnormalities in RA patients and in arthritis models have been reported. However, it remains unclear when these abnormalities occur and where they are distributed. In this study, we analyzed spatiotemporal changes in gene expression in the brains of mice with collagen-induced arthritis (CIA). METHODS: Mice were divided into three groups: (i) CIA (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 ten stages of arthritis and divided into six sections. Real-time polymerase chain reaction was performed using RNA extracted from the brain, and the expression of proinflammatory cytokines and glial markers was semi-quantified. Arthritis score, body weight, and food and water intakes were recorded and analyzed for correlations with brain gene expression. We also investigated the effect of interleukin-6 (IL-6) injection in the olfactory bulbs (OBs) on the food intake. RESULTS: After booster immunization, a transient increase in Integrin subunit α-M and IL-1ß was observed in multiple areas in CIA. IL-6 is persistently expressed in the OB before the onset of arthritis, which is correlated with body weight loss and decreased food intake. This change in the OB was observed in the C(+/-) but not in the C(-/-) groups. In the C(+/-) group, non-arthritic mice showed the same changes in the OB as the arthritic mice. This elevation in IL-6 levels persisted throughout the chronic phase until day 84. In addition, IL-6 injection into the OB reduced food intake. 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, including appetite loss, which is present in the early stages of the disease and manifests as a variety of symptoms over time.

Sustained microglial activation in the area postrema of collagen-induced arthritis mice.

BACKGROUND: Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). METHODS: Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1ß (IL-1ß) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. RESULTS: Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1ß-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1ß expression in brain regions containing the AP. CONCLUSIONS: Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.

Therapeutic effects of sunitinib, one of the anti-angiogenetic drugs, in a murine arthritis.

OBJECTIVES: The purpose of this study was to confirm the inhibitory effects of sunitinib, an angiogenesis inhibitor that targets tyrosine kinases of vascular endothelial growth factor receptor (VEGFR) family and platelet-derived growth factor receptor (PDGFR) family, on arthritis in mice with type II collagen-induced arthritis (CIA). METHODS: Sunitinib at a concentration of 30 or 60 mg/kg/day was intraperitoneally administered to mice with CIA. We compared the changes in arthritis score over time, pathological score, bone density, and microvascular density in synovial membrane between the vehicle and treatment groups. RESULTS: In the sunitinib-treated groups, the arthritis score decreased in a dose-dependent manner in comparison with that in the vehicle group. Furthermore, improvement in the pathological score, inhibitory tendency of loss in the bone density, and a decrease in the synovial microvascular density were also observed in the sunitinib-treated groups. CONCLUSIONS: Sunitinib remarkably inhibited arthritis, particularly synovial angiogenesis in a murine CIA model. This compound may be useful for treating arthritis.