Lipoxin A4 depresses inflammation and promotes autophagy via AhR/mTOR/AKT pathway to suppress endometriosis

Abstract

Background: Endometriosis is a benign gynecological disease with the feature of estrogen dependence and inflammation. The function of autophagy and the correlation with inflammation were not yet revealed.Methods: Autophagosomes were detected by transmission electron microscopy.Gene Expression Omnibus (GEO) database was referred to analyze the expression of autophagy-related genes. Quantification of mRNA and protein expression was examined by qRT-PCR and Western Blot. Immunohistochemistry was performed to explore the expression of proteins in tissues. The mouse model of endometriosis was performed to analyze the autophagic activity and effect of LXA4. Results:The expression of autophagy-related genes in endometriotic lesions were unusually changed. The number of autophagosomes and LC3B-II expression was diminished, and p62 was increased in ectopic lesions from both patients and mice.Interleukin 1β (IL1β) attenuated the expression of LC3B and promoted the level p62.The autophagy activator MG-132 upregulated the expression of LC3B and reduced IL1β, IL6, and p62. LXA4 reversed the inhibitory effect of IL1β on the expression of LC3B and p62, and blocking the receptor of LXA4 AhR (aryl hydrocarbon receptor) resulted in the incapacitation of LXA4 to influence the effect of IL1β. LXA4 depressed the phosphorylation of AKT and mTOR to against IL1β, and blocking AhR negatively regulated the effect of LXA4 on AKT/mTOR pathway. LXA4 reduced the ectopic lesions and the expression of IL1β and p62, but enhanced LC3B-II in endometriotic mouse models. Conclusion:In endometriosis, increased inflammation of ectopic lesions prominently depresses autophagy. LXA4 could regulate autophagy by suppressing inflammatory response through AhR/AKT/mTOR pathway.

Potential shared pathogenic mechanisms between endometriosis and inflammatory bowel disease indicate a strong initial effect of immune factors

“…An increasing number of studies have shown that both EM and IBD involve activation of immune and inflammatory pathways ( 32 , 33 ). During the progression of EM, specific anti-inflammatory cytokines (IL-1 beta, IL-5, IL-6, IL-7, IL-12, IL-4, and IL-10) and immune cells (M2 macrophage, neutrophil, M1 macrophage, and activated mast cells) are critical in supporting the persistence, expansion, infiltration, differentiation, angiogenesis, and immune evasion of endometriotic lesions in a multitude of pathogenic ways ( 34 – 37 ).…”

The mysterious association between adiponectin and endometriosis

“…Autophagy promotes the phagocytosis of apoptotic bodies and degradation of lysosomes ( Mariño et al, 2014 ); therefore, decreased autophagic activity in ectopic and eutopic endometrial cells would lead to a decrease in apoptosis ( Choi et al, 2014 ; Yu et al, 2016 ). As mTOR is a major negative regulator of autophagy, several studies have reported that cellular autophagy can be induced by inhibiting the mTOR signaling pathway in ectopic endometrial cells ( Choi et al, 2015 ; Xu H. et al, 2019 ; Huang et al, 2023 ). In addition, in mouse models of EMs, in addition to inhibiting autophagy, the upregulation of mTOR in EMs tissues promoted the survival of ectopic endometrial cells ( Yang et al, 2017 ).…”