Macrophage-specific PLA2g6 deficiency exacerbates liver injury during bacterial sepsis via myelopoiesis activation in male mice

Background PLA2g6 mutations lead to neurodegeneration and Parkinson’s disease and polymorphisms of PLA2g6 are associated with increase of serum C-reactive protein. Hepatic inflammation was exaggerated in PLA2g6-null mice during autoimmune hepatitis and NASH. The role of PLA2g6 in macrophages (MΦ) is still elusive. Here, we studied the response of MΦ-specific PLA2g6 deficient (KO) mice to E.Coli lipopolysaccharide (LPS) treatment.

Methods Male PLA2g6 flox and KO mice were subjected to treatment with a single (1 mg/kg, 24 h) or multiple (1 mg/kg daily, 4 times) doses of LPS as a model of acute and persistent inflammation, respectively. Complete blood counts, plasma cytokines, and liver histology were analysed.

Results Without LPS treatment, MΦ-specific PLA2g6 deficiency led to an increase in spleen weights, plasma IL-6, blood mean platelet volume, hepatic necrosis, and ~25% of KOs showed hepatic lymphoplasmacellular infiltration. Acute LPS caused the elevation of plasma IL-6, IL-10, KC, GM-CSF, MCP-1, and MIP1-α, the deficiency further elevated MIP1-α levels. After persistent LPS, KOs at 6 months old showed an increase in blood granulocytes and eosinophils without severe hepatic injury. KOs at 12 months old showed an increase in plasma AST, hepatic necrosis, and interstitial infiltration of immune cells.

Conclusions MΦ-specific PLA2g6 deficiency caused basal inflammatory abnormalities seen in blood, spleen, and liver. The deficiency further increased plasma MIP1-α resulting in an increase in myelopoiesis after acute and persistent LPS, respectively. The observed bacterial innate immune response demonstrated the effects of MΦ-PLA2g6 deficiency on hepatic inflammation which can lead to liver failure during sepsis.

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Artikel online veröffentlicht:
26. Januar 2022