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

Abstract

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-1β (IL-1β) 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-1β-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1β 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.

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

“…According to previous animal and clinical studies, neuroinflammation may be caused by inflammation of several peripheral organs such as colitis, PD, gastritis, pancreatitis, arthritis, cystitis, atopic dermatitis, PBC, CFS/ME, and COPD ( Lin et al, 2018 ; Albaret et al, 2020 ; Ding et al, 2020 ; Furutama et al, 2020 ; Matsushita et al, 2021 ; Shin et al, 2021 ). Given the neuropsychiatric symptoms and the results of biochemical experiments, research has identified that the hippocampus, cortex, amygdala, and hypothalamus are most affected by peripheral-induced neuroinflammation ( Reichmann et al, 2015 ; Riazi et al, 2015 ; Zonis et al, 2015 ; Do and Woo, 2018 ; Han et al, 2018 ; Peppas et al, 2021 ).…”

“…Other animal models have been used to illustrate the relationship between inflammatory diseases and neuroinflammation, such as periodontal disease (PD), gastritis, pancreatitis, arthritis, cystitis, and atopic dermatitis ( Lin et al, 2018 ; Albaret et al, 2020 ; Ding et al, 2020 ; Furutama et al, 2020 ; Matsushita et al, 2021 ; Shin et al, 2021 ). The inflammation regions in the brain and neuropsychiatric symptoms for these studies are listed in Table 2 .…”

Attenuation of widespread hypersensitivity to noxious mechanical stimuli by inhibition of GABAergic neurons of the right amygdala in a rat model of chronic back pain

“…Error bars indicate the standard error of the mean persistent widespread hypersensitivity. Another possibility to examine in a future study is the sustained microglial activation in the area postrema, as shown in mice with collagen-induced arthritis(Matsushita et al, 2021), which may produce the release of cytokines in the brain and contribute to the present findings.…”

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 ).…”