α7nAChR enhances autophagy and alleviates meningitis via the p53-USP33-ULK1 signaling pathway

Dysregulated autophagy contributes to the pathogenesis of numerous infectious diseases, including bacterial meningitis, but the underlying mechanisms and the targeted interventions remain uncertain. This study reveals that reduced acetylcholine levels are associated with suppressed autophagy in Listeria monocytogenes (LM)-induced meningitis. Activation of cholinergic receptor signaling with the Alpha 7 nicotinic acetylcholine receptor ( α 7nAChR) agonist GTS-21 reverses LM infection-suppressed autophagy and protects mice from meningitis. Mechanistically, LM infection downregulates the expression of unc-51 like autophagy activating kinase (ULK1), an essential autophagy initiation protein, in both neurons and microglial cells, leading to impaired autophagy and subsequent immune dysregulation and neurological damage. Engagement of α 7nAChR by GTS-21 enhances the transcription of deubiquitinase ubiquitin specific peptidase 33 (USP33) via the transcription factor Tumor protein p53 (p53). USP33 then removes K48-linked ubiquitination from the ULK1 protein, thereby restoring ULK1-mediated autophagy. Consequently, α 7nAChR enhanced autophagy re-establishes neuroimmune homeostasis and promotes bacterial clearance during meningitis. These findings uncover a previously unknown mechanism through which cholinergic signaling regulates autophagy through the p53-USP33-ULK1 axis to alleviate LM-induced meningitis, thereby offering potential intervention strategies for targeted autophagy modulation in neuroimmune disorders.