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Sex-dimorphic role of neutrophil-derived COX-2 in protecting against hepatic ischemia–reperfusion injury
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DOI：10.1016/j.apsb.2026.07.048.png)
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Abstract
En 中文
Hepatic ischemia–reperfusion (IR) injury is a major complication of liver transplantation, often leading to graft dysfunction and poor outcomes. Sterile inflammation involving diverse immune cells is a hallmark of hepatic IR injury, but the molecular mechanisms of their functions remain incompletely understood. Our single-cell RNA sequencing (scRNA-seq) analyses revealed an upregulation of Ptgs2 (the gene encoding cyclooxygenase-2, COX-2), which was predominantly expressed by neutrophils among hepatic immune cells after IR injury. Notably, neutrophil-specific deletion of Ptgs2 exacerbated hepatic IR injury. Interestingly, this effect was observed only in female mice, but not males. Ovariectomy and estrogen supplementation experiments further confirmed an estrogen-dependent protective function of neutrophil-derived COX-2. Mechanistically, we found that neutrophils from female mice exhibited higher COX-2 expression and greater prostacyclin (PGI2) production than those from male mice. Pharmacological administration of a PGI2 analog or blockade of the PGI2 receptor demonstrated that the protective effect of PGI2 was mediated through the induction of heme oxygenase-1 (HO-1) during liver IR injury. In conclusion, our findings reveal a previously unrecognized neutrophil-specific and female-restricted protective function of COX-2 signaling, dependent on estrogen and associated with activation of the COX-2/PGI2/HO-1 pathway, in hepatic IR injury. These findings provide new mechanistic insights into the pathophysiology of IR injury and highlight potential therapeutic strategies for improving outcomes in liver transplantation.
Keywords:
Hepatic ischemia–reperfusion injury
Neutrophils
Cyclooxygenase-2
Ptgs2
Sex dimorphism
Estrogen
Prostacyclin
Heme oxygenase-1
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