Sustained Microglial Activation in the Area Postrema of Collagen-induced Arthritis Mice: a Potential Pathway Linking Arthritis and the Brain

Abstract

Background. Neuropsychological symptoms are common complications among patients with rheumatoid arthritis (RA), while it is largely unexplored how RA pathology spread to brain protected by blood-brain barrier (BBB). The sensory circumventricular organs (sCVOs) (brain regions lacking a blood–brain barrier) is the brain site that peripheral inflammatory signals, such as blood cytokines and chemokines, can directly access and modulate cell activities in the brain parenchyma. To determine whether microglia, resident immune cells in neuronal tissue, in the sCVOs can function as an interface between peripheral inflammation and brain under the autoimmune-arthritis conditions, we analyzed microglia in the sCVOs of a mouse model of collagen-induced arthritis (CIA).Methods. Microglial number and morphology were analyzed in the sCVOs of CIA and control mice (controls were administrated Freund’s adjuvant [FA] and/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 on microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression in microglia was also analyzed by multiple fluorescent in situ hybridization.Results. In the area postrema (AP), one of the sCVOs located in the medulla, microglia significantly increased in density (CIA, n = 15; FA, n = 6; saline: n = 10) with changes in morphology during the establishment and chronic phases. In other sCVOs (subfornical organs [SFO] and organum vasculosum laminae terminalis [OVLT]), microglial changes were not significant. In the AP microglia, non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of microglia in a highly activated form was increased in the CIA group. Also, the density of IL-1β-positive microglia, a hallmark of functional activation, increased in the AP. These microglial changes in the AP persisted until the chronic phase.Conclusions. Our findings indicate that an increase and activation of microglia is sustained in the AP during chronic arthritis. This suggests that there is a direct physiological pathway linking peripheral arthritis to the brain through the AP.

Research progress on rheumatoid arthritis-associated depression

“…Third, blood-derived immune cells and pro-inflammatory cytokines can access the brain through a damaged BBB (Süß et al, 2020). A recent study found that microglia in the area postrema (a brain region lacking a BBB) significantly increased in density and kept highly activated during persistent autoimmune arthritis, which demonstrates that chronic inflammation in RA may affect microglia in brain regions lacking a BBB and result in CNS-mediated symptoms, such as depression (Matsushita et al, 2021).…”