5-HT₇R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination

Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear.

Here we found a neuroimmune way that prevents infection-induced tissue damage.

By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation.

Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT₇R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT₇R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT₇R-mediated CCR5 degradation.

Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT₇R-CCR5 axis as a potential target to promote neuroimmune resilience.