The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.

Keywords: blood-brain barrer; depression; microglia; neurodegenenerative diseases; neuroinflammation; rheumatoid arthritis.

Figure 1

Propagation of chronic peripheral inflammation into the central nervous system (CNS). Rheumatoid arthritis (RA) comprises a spectrum of different peripheral immunophenotypes, including a lymphoid subtype driven by adaptive immune activation and a myeloid subtype characterized by the activation of myeloid cells. While the lymphoid subtype is represented by the mouse model of collagen-induced arthritis (CIA), the human TNF-α transgenic (hTNFtg) mouse model mimicks key aspects of the myeloid form of RA. Peripheral inflammation can reach the CNS via different gateways, including the vagus nerve, the somatosensory nervous system, the meninges, the choroid plexus and the bloodstream. In both lymphoid and myeloid models of RA, the activation of microglia, astrocytes, and perivascular macrophages as well as increased levels of pro-inflammatory cytokines and chemokines were described. While in CIA, these alterations were mainly observed in the cortex (Ctx) and hippocampus (Hc), hTNFtg mice show a distinct regional distribution of neuroinflammation including the Ctx, striatum (Str), and thalamus (Th), but sparing the Hc and the cerebellum (Cb). The blood-brain barrier (BBB) was proposed to be disrupted in lymphoid models, potentially allowing the influx of blood-derived immune cells. In myeloid models, BBB integrity appears maintained, but endothelia display an activated signature and may contribute to the secretion of cytokines and chemokines. Neuroinflammation in RA models was linked with impaired neuronal function due to altered neurotransmitter metabolism and neural plasticity as well as synaptic and network refinement. Ultimately, these changes may cause neuropsychiatric symptoms. So far, behavioral phenotypes were mainly found in lymphoid models of RA and are limited in the myeloid subtype. Figure created with BioRender (https://biorender.com).