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

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 1ß (IL1ß) attenuated the expression of LC3B and promoted the level p62. The autophagy activator MG-132 upregulated the expression of LC3B and reduced IL1ß, IL6, and p62. LXA4 reversed the inhibitory effect of IL1ß 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 IL1ß. LXA4 depressed the phosphorylation of AKT and mTOR to against IL1ß, and blocking AhR negatively regulated the effect of LXA4 on AKT/mTOR pathway. LXA4 reduced the ectopic lesions and the expression of IL1ß 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.

A multifunctional nanoparticle for efferocytosis and pro-resolving-mediated endometriosis therapy.

Endometriosis is an inflammation-dependent disorder characterized by the abnormal growth of endometrium-like lesions. In recent years, there is a great deal of interest in the development of anti-inflammatory therapy. Herein, an acid-sensitive calcium carbonate nanoparticle (CaNP) incorporated BML-111 (BML@CaNP) was prepared. BML@CaNP acted as a Ca2+ nanomodulator for efferocytosis (macrophages engulf apoptotic cells). Specifically, BML@CaNP induced the apoptosis of endometriotic stromal cells and enhanced the efferocytosis of macrophages. In addition, the particle can also deliver BML to the ectopic lesion for resolving the inflammatory response. In vivo BML@CaNP effectively suppressed lesion growth in endometriosis mice model, which could be attributed to the enhancing efferocytosis of cells and the lower levels of inflammatory factors in peritoneal fluid. In addition, these nanoparticles did not show side effects. In all, we provide a new anti-inflammatory strategy by both enhancing efferocytosis and resolving inflammation for the treatment of endometriosis.