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

Abstract

INTRODUCTION: Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. OBJECTIVES: Here we found a neuroimmune way that prevents infection-induced tissue damage. METHODS: 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. RESULTS: Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HTR, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HTR 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-HTR-mediated CCR5 degradation. CONCLUSION: Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HTR-CCR5 axis as a potential target to promote neuroimmune resilience.