Over-excitation of tyrosine hydroxylase neurons in the paraventricular nucleus of the hypothalamus drives a neuroimmune positive feedback loop in rheumatoid arthritis.

BACKGROUND

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and pain, leading to a significant decline in patients' quality of life. Recent studies suggest that the central nervous system (CNS) may also contribute to disease progression by modulating autonomic and immune functions. However, the precise mechanisms underlying CNS involvement remain unclear.

OBJECTIVE

This study aims to investigate the alterations in the functional state of tyrosine hydroxylase (TH) within the paraventricular nucleus (PVN) in RA and to explore their potential role in regulating peripheral immune responses.

METHODS

An adjuvant-induced arthritis (AA) mouse model was employed. Changes in PVN-TH neuron excitability were assessed using double immunofluorescence staining, whole-cell patch-clamp recording, and in vivo calcium imaging. Chemogenetic inhibition of PVN-TH neurons was performed to evaluate behavioral manifestations of RA, such as paw swelling, paw withdrawal latency, and joint scoring, as well as the concentration of NE released from sympathetic nerve endings in the popliteal lymph nodes and subsequent immune responses in the popliteal lymph nodes, including T cell proliferation and dendritic cell activation.

RESULTS

AA mice displayed pronounced hyperactivity of PVN-TH neurons, as indicated by increased c-Fos+ expression, higher action potential firing frequency, and elevated calcium signal amplitudes. Targeted inhibition of these neurons significantly reduced inflammatory symptoms and the concentration of NE released from sympathetic nerve endings in the popliteal lymph nodes, and decreased T cell proliferation and dendritic cell activation in the popliteal lymph nodes.

CONCLUSION

In the RA model, pathological hyperactivity exhibited by PVN-TH neurons may be involved in peripheral immune regulation through central sensitization and inflammatory signaling. These neurons may be key hubs driven by the central nervous system, providing new insights into neuroimmune mechanisms and potential targets for neuroimmunotherapy in RA.