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

Chiara Agostinis, Sonia Zorzet, Andrea Balduit, Gabriella Zito, Alessandro Mangogna, Paolo Macor, Federico Romano, Miriam Toffoli, Beatrice Belmonte, Gaia Morello, Anna Martorana, Annamaria Martorana, Violetta Borelli, Giuseppe Ricci, Uday Kishore, Roberta Bulla
Frontiers in immunology · 2021 · vol. 12 , pp. 693118 · doi:10.3389/fimmu.2021.693118 · PMID:34489939 · W3195381101
article OA: gold CC0 ⤵ 18 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Endometriotic lesions locally synthesize complement component C3, which drives mast cell activation and cyst formation through an auto-amplifying inflammatory loop.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study investigated how the complement component C3 is produced and functions in endometriotic tissue, focusing on interactions between C3 and mast cells (MCs). Using immunofluorescence and RT-qPCR in cells isolated from endometriosis lesions and comparing wild-type versus C3 knockout mice in a murine endometriosis model, the authors found locally synthesized C3 in ectopic tissue but not eutopic tissue, and that wild-type mice developed more cyst formation with more degranulated mast cells and higher C3a activity than C3-deficient mice. The paper proposes an auto-amplifying loop in which C3a drives mast cell infiltration and activation, contributing to lesion pathogenicity, while noting a limitation of the model that it did not produce deeply infiltrating lesions. This paper is centrally about endometriosis — it tests whether local C3/C3a signaling promotes mast-cell–mediated inflammation and lesion engraftment.

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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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Cell Degranulation Complement C3 Endometriosis Endometrium Inflammation Mediators Mast Cells Peritoneal Diseases Animals Case-Control Studies Coculture Techniques Complement C3 Complement C3 Complement C3a Complement C3a Disease Models, Animal Endometriosis Endometriosis Endometriosis Endometrium Endometrium

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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