Background: The Toll-like receptor (TLR) plays an important role in the induction of the hyperinflammatory response and tissue injury in sepsis. The cholinergic antiinflammatory pathway serves as a link between the parasympathetic and innate immune systems. We examined the antiinflammatory effect of nicotine, a potent α7 nicotinic acetylcholine receptor (α7nAChR) agonist, with regard to TLR expression and signaling during sepsis.
Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). The subjects received intraperitoneal nicotine (400 μg/kg) immediately after CLP for the biochemical study and 0, 24, 48, and 72 hours after CLP for the survival test. Intraperitoneal methyllycaconitine (MLA; 5 mg/kg), an α7nAChR antagonist, was administered 5 minutes prior to nicotine treatment. We evaluated the effects of nicotine using α7nAChR and phosphoinositide 3-kinase (PI3K) inhibitors in lipopolysaccharide-stimulated RAW264.7 cells.
Results: Nicotine improved sepsis-induced mortality, attenuated organ failure, and suppressed inflammatory cytokines, which were abolished by MLA. Nicotine enhanced PI3K/Akt activation and reduced PU.1 activity and TLR4 expression. MLA and PI3K inhibitors blocked this effect of nicotine.
Conclusions: Our findings suggest that stimulation of the cholinergic antiinflammatory pathway by nicotine protects against septic injury and that this may be associated with inhibition of TLR4 expression via α7nAChR/PI3K signaling.
Keywords: PI3K; PU.1; TLR; nicotine; sepsis; α7nAChR.