IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype
Yosuke Ono1,2, Osamu Yoshino3, Takehiro Hiraoka4
1Department of Obstetrics and Gynecology, University of Toyama, Toyoma, Japan.
Abstract:
In endometriosis, M2 macrophages (MΦ) are dominant and promote the development of endometriosis lesions. However, the factor(s) which induces M2 MΦ are unknown. In the present study, we focused on interleukin (IL)-33, known as an alarmin and investigated its expression and its role in endometriosis, especially from the point of the relevance with MΦ. The expression of IL-33 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors was obtained and used to measure IL-33 concentration. Endometriotic stromal cells (ESC) and MΦ derived from patients were used for in vitro experiments. IL-33 was detected in the epithelium and stromal cells of endometriotic lesions. The mean IL-33 concentration in the cystic fluid of endometriomas was significantly higher than that in non-endometriomas (2.2 ng/ml vs. 0.02 ng/ml, P < 0.01). IL-1β induced IL-33 mRNA expression in ESC via p38 MAPK activation. With IL-33 stimulation, peritoneal MΦ polarized to M2 MΦ and produced IL-1β mRNA with a 2.2-fold increase, which was negated with soluble ST2, a decoy receptor of IL-33. IL-33, derived from endometriotic lesions, stimulated MΦ to produce IL-1β, which results in increasing IL-33 production in ESC. This cycle may continue to exacerbate the endometriotic lesions.
Insights
Interleukin-33 (IL-33) drives M2 macrophage polarization in endometriosis, promoting lesion growth. This study reveals a cycle where IL-33 from lesions stimulates macrophages, exacerbating the condition.
Area of Science:
- Reproductive immunology
- Cellular and molecular biology
Background:
- M2 macrophages are dominant in endometriosis and promote lesion development.
- The specific factors inducing M2 macrophage polarization in endometriosis remain largely unknown.
Purpose of the Study:
- To investigate the role of interleukin-33 (IL-33), an alarmin, in endometriosis.
- To explore the relationship between IL-33 and macrophage polarization in the context of endometriosis.
Main Methods:
- Immunohistochemistry to detect IL-33 expression in endometriotic lesions.
- Measurement of IL-33 concentration in cystic fluid from endometriomas and non-endometriomas.
- In vitro experiments using endometriotic stromal cells (ESC) and patient-derived macrophages (MΦ).
Main Results:
- IL-33 was detected in the epithelium and stromal cells of endometriotic lesions.
- Significantly higher IL-33 concentrations were found in endometrioma cystic fluid compared to non-endometriomas.
- IL-33 stimulation induced peritoneal MΦ to polarize to M2 phenotype and increase IL-1β mRNA expression, an effect blocked by soluble ST2.
Conclusions:
- IL-33, originating from endometriotic lesions, promotes M2 macrophage polarization and IL-1β production.
- A positive feedback loop involving IL-33 and IL-1β may contribute to the exacerbation of endometriosis lesions.
