Myeloid-specific deficiency of group VIA calcium-independent phospholipase A2 preconditions myeloid cells for injury resolution after acetaminophen exposure

Feng Xu; Chutima Jansakun; Gang Li; Uddipta Biswas; Gernot Poschet; Simone Staffer; Sabine Tuma-Kellner; Inaam Nakchbandi; Uta Merle; Walee Chamulitrat

doi:10.1016/j.biopha.2025.118146

Myeloid-specific deficiency of group VIA calcium-independent phospholipase A2 preconditions myeloid cells for injury resolution after acetaminophen exposure

Biomed Pharmacother. 2025 Jun:187:118146. doi: 10.1016/j.biopha.2025.118146. Epub 2025 May 8.

Authors

Affiliations

¹ Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany; Gastrointestinal Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, PR China.
² Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany; School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand.
³ Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
⁴ Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany.
⁵ Metabolomics Core Technology Platform, Centre for Organismal Studies, University of Heidelberg, Heidelberg 69120, Germany.
⁶ Max-Planck Institute of Biochemistry and University of Heidelberg, Im Neuenheimer Feld 305, Heidelberg 69120, Germany.
⁷ Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany. Electronic address: Walee.Chamulitrat@med.uni-heidelberg.de.

PMID: 40344700
DOI: 10.1016/j.biopha.2025.118146

Abstract

Genetic PLA2G6 variants are associated with C-reactive protein in humans. Myeloid-specific PLA2G6-deficient (Pla2g6^M-/-) mice show increased hepatic myeloperoxidase and recruitment of granulocytes in response to lipopolysaccharide (LPS). We hypothesized that Pla2g6^M-/- mice could be protected from acetaminophen (APAP) hepatotoxicity whereby neutrophils, eosinophils, and alternatively activated macrophages are reportedly protective. Herein, Pla2g6^M-/- mice treated with 300 mg/kg APAP for 24 h showed attenuated hepatic necrosis and plasma cytokines, and with elevated levels of Ly6C^lo in peripheral blood mononuclear cells and plasma lipoxin A4. Remarkably, bone-marrow-derived macrophages (BMDMs) from untreated Pla2g6^M-/- mice exhibited elevated baseline expression of cPLA2α, NOX2, Rac1, Arg-1, phospho-MLKL, and iNOS protein, which was exacerbated by LPS in vitro. APAP administration preconditioned Pla2g6^M-/- BMDMs for further activation of enzymes involving in phagocytosis (Rac1 and phospho-MLKL) and eicosanoids (COX2 and A15LOXB). Pla2g6^M-/- BMDMs showed an increased release of pro-resolution lipid mediators lipoxin A4, PGE2, and 15d-PGJ2, which was further elevated by LPS in vitro or APAP in vivo. Phagocytic gene signatures (myeloperoxidase and NOX2) were also upregulated in livers of untreated and APAP-treated Pla2g6^M-/- mice. APAP protection in Pla2g6^M-/- mice was associated with increased proportion of neutrophils (Ly6G), eosinophils (eosinophilic cationic protein), and M2 macrophages (CD206) in/at the portal tract and central vein as determined by immunohistochemistry. Thus, myeloid-specific PLA2G6 deficiency preconditioned macrophages for eicosanoid and phagocytic pathways rendering protection against APAP hepatotoxicity. Our results may be applicable to patients with PLA2G6 mutations, and PLA2G6 inhibition specifically in myeloid cells may represent a new strategy to alleviate APAP poisoning.

Keywords: NADPH oxidase 2; cPLA2α; myeloid-PLA2G6; myelopoiesis; paracetamol toxicity; pro-resolving eicosanoids; tissue resolution.

MeSH terms

Acetaminophen* / toxicity
Animals
Chemical and Drug Induced Liver Injury* / enzymology
Chemical and Drug Induced Liver Injury* / genetics
Chemical and Drug Induced Liver Injury* / pathology
Chemical and Drug Induced Liver Injury* / prevention & control
Cytokines / blood
Group VI Phospholipases A2* / deficiency
Group VI Phospholipases A2* / genetics
Group VI Phospholipases A2* / metabolism
Liver / drug effects
Liver / enzymology
Liver / pathology
Macrophages / drug effects
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells* / drug effects
Myeloid Cells* / enzymology
Myeloid Cells* / metabolism
Myeloid Cells* / pathology
Phagocytosis / drug effects

Substances

Acetaminophen
Group VI Phospholipases A2
Pla2g6 protein, mouse
Cytokines