Activation of α7 nicotinic acetylcholine receptors inhibits hepatic necroptosis and ameliorates acute liver injury in mice

Acute liver injury (ALI) is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate ALI and investigate its possible mechanisms.

ALI was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type (WT), α7nAChR knockout (α7nAChR ^-/-) and Sting mutation (Sting^gt/gt) mice in the presence or absence of a pharmacological selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis and infiltration of immune cells during ALI were assessed.

The expression of α7nAChR in liver tissue was increased in LPS/D-Gal induced ALI mice. Compared to the age-matched WT mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacological activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45⁺CD11b^hiF4/80^int), M1 macrophages (CD45⁺CD11b⁺F4/80⁺CD86 ^hiCD163^low), Ly6C^hi monocytes (CD45⁺CD11b⁺MHCⅡ ^lowLy6C ^hi), but increased the resident Kupffer cells (CD45⁺CD11b^intF4/80 ^hiTIM4 ^hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR.

Our study revealed that activating α7nAChR could protect against LPS/D-Gal induced ALI by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.