Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

Abstract

According to a rich body of literature, immune cell dysfunctions, both locally and systemically, and an inflammatory environment characterize all forms of endometriosis. Alterations in transcripts and proteins involved in the recruitment of immune cells, in the interaction between cytokines and their receptors, cellular adhesion and apoptosis have been demonstrated in endometriotic lesions. The objective of this narrative review is to provide an overview of the components and mechanisms at the intersection between inflammation and genetics that may constitute vanguard therapeutic approaches in endometriosis. The GWAS technology and pathway-based analysis highlighted the role of the MAPK and the WNT/β-catenin cascades in the pathogenesis of endometriosis. These signaling pathways have been suggested to interfere with the disease establishment via several mechanisms, including apoptosis, migration and angiogenesis. Extracellular vesicle-associated molecules may be not only interesting to explain some aspects of endometriosis progression, but they may also serve as therapeutic regimens per se. Immune/inflammatory dysfunctions have always represented attractive therapeutic targets in endometriosis. These would be even more interesting if genetic evidence supported the involvement of functional pathways at the basis of these alterations. Targeting these dysfunctions through next-generation inhibitors can constitute a therapeutic alternative for endometriosis.

Whole-Tissue Deconvolution and scRNAseq Analysis Identify Altered Endometrial Cellular Compositions and Functionality Associated With Endometriosis

“…Previous bulk RNAseq and microarray analyses revealed altered transcriptomic profiles in the eutopic endometrium of women with versus without endometriosis ( 3 – 5 ). With disease, the eutopic endometrium displays a pro-inflammatory transcriptomic feature and fails to elicit normal steroid hormone responses that are essential for endometrial transformation ( 4 , 6 – 8 ). This pro-inflammatory feature was also observed in the microarray and RNAseq profiles of isolated endometrial stromal fibroblasts (eSFs), mesenchymal stem cells (eMSCs), and macrophages ( 9 , 10 ).…”

The Role of Selected Chemokines in the Peritoneal Fluid of Women with Endometriosis—Participation in the Pathogenesis of the Disease

“…The presence of endometrial cells in an ectopic location causes a natural response of innate and adaptive immune system components, which try to eliminate menstrual debris and initiate tissue repair. However, the inability to deal with the persistent presence of menstrual debris over time may lead to immune system overload and subsequent immune alterations [27]. This can aggravate the inflammatory process and transform it into a chronic state.…”

Increased ApoE Expression in Follicular Fluid and the ApoE Genotype Are Associated With Endometriosis in Chinese Women

“…First, previous studies have shown that inflammation is the central process in EMT, which can lead to pain, fibrosis, adhesion formation, and infertility ( 2 , 27 ). Inflammation plays an important role in the etiology and pathophysiology of EMT ( 28 , 29 ). Furthermore, ApoE-ϵ4 is reportedly associated with higher levels of inflammation ( 18 ).…”