The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

Abstract

The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.

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

“…Previous studies have shown that the TLR4-C3 axis can regulate intestinal immune responses during chronic colitis ( 41 ). Research byAgostinis C identified the inflammatory feed-foward loop triggered by complement component C3 may serve as a potential therapeutic target for endometriosis ( 42 ). Rijcken E et al.…”

Identification and Analysis of Potential Immune-Related Biomarkers in Endometriosis

“…ROC analysis revealed that four IRGs can be used as potential biomarkers of endometriosis, which also demonstrated the feasibility in terms of the AUC, a signal for endometriosis occurrence. Recently, C3 was considered a candidate diagnostic biomarker of endometrosis, and its expression was correlated with the engraftment of the endometriotic cysts [ 45 ]. The overexpression of VCAM-1 on the peritoneum of endometriosis had been revealed by Schutt et al [ 46 ].…”

“…The TF-IRG network could be used to present novel prospective molecular mechanisms underlying the development of tumors [ 45 ]. However, studies of the regulatory mechanisms underlying TFs and IRGs in endometriosis are still in progress.…”

“Iron triangle” of regulating the uterine microecology: Endometrial microbiota, immunity and endometrium

“…The key step for activating the complement system by recognizing non self-molecules is to activate the central C3 component through the classical pathway (antibody mediated), lectin pathway or alternative pathway ( 91 ). C3 is also present in the epithelial cells of the endometrium ( 92 ). Activation of C3 on the cell surface can stimulate the formation of membrane attack complexes on NEUs and target cells, resulting in cell damage and cell lysis, but other host cells are protected by membrane binding regulatory molecules such as CD46, CD55 and CD59 ( 93 ).…”