Inhibitory effect of baricitinib on microglia and STAT3 in a region with a weak blood-brain barrier in a mouse model of rheumatoid arthritis

Objectives: In patients with rheumatoid arthritis (RA), baricitinib not only improves arthritis symptom severity, but also patients' neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema (AP), which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the AP. Therefore, we sought to assess the effect of baricitinib on microglia in the AP using collagen-induced arthritis mouse model.

Methods: Microglia number and morphology in the AP were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the AP was also immunohistochemically examined. Behavioral outcomes were assessed by examining feeding behaviors and sucrose preference tests.

Results: In the early phase, activated microglial levels in the AP were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase.

Conclusion: Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviors during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.

JAK-STAT; Rheumatoid arthritis; area postrema; baricitinib; circumventricular organs; collagen-induced arthritis; depression; microglia; neuroinflammation; phosphorylated STAT3.