ACR-16/α7-nicotinic receptor signaling mediates nicotine-induced mitochondrial dysfunction and suppression of host defense against gram-negative bacteria.

Smoking, alongside e-cigarette and heated tobacco use, impairs immune function and increases susceptibility to infections, primarily due to nicotine's disruption of cellular processes. While mitochondria are traditionally associated with bioenergetics, they also serve as critical regulators of immunity, with mitochondrial dysfunction linked to compromised host defenses. To investigate nicotine's effects on mitochondrial function and immunity, we utilized Caenorhabditis elegans infected with Pseudomonas aeruginosa or Staphylococcus aureus. Acute nicotine exposure elicited pathogen-specific effects. Specifically, it enhanced immune responses and survival against S. aureus, but suppressed host defense mechanisms and mitochondrial responses against P. aeruginosa. These impairments were characterized by reduced bacterial clearance, impaired avoidance behavior, abnormal ROS production, and disrupted mitochondrial activity. Mechanistically, nicotine exerted its immunomodulatory effects through ACR-16/α7-nicotinic receptor signaling, as its absence abrogated both the beneficial and detrimental outcomes. Proteomic analysis revealed nicotine-induced mitochondrial dysfunction, disrupting the TCA cycle, and ATP synthesis. Upon P. aeruginosa infection, nicotine suppressed the mitochondrial unfolded protein response (mtUPR) and its associated immune functions. Pharmacological or genetic activation of mtUPR restored immune function and improved survival during P. aeruginosa infection. These novel findings highlight the essential role of mitochondrial health in regulating immune responses and propose mtUPR activation as a potential strategy to mitigate nicotine-induced immunotoxicity.