Abstract
Endometriosis is a debilitating gynecological disease characterized by the extrauterine presence of endometrial-like tissues located on the peritoneal membrane and organs of the pelvic cavity. Notably, dysfunctional immune activation in women with endometriosis could also contribute to the development of disease. In particular, alternatively activated (M2) peritoneal macrophages are shown to aid peritoneal lesion development by promoting remodeling of extracellular matrix and neovascularization of lesions. However, the stimuli responsible for polarizing M2 macrophages in endometriosis remain elusive. Interleukin-17A (IL-17A) can induce M2 macrophage polarization in other disease models and IL-17A is elevated in the plasma and endometriotic lesions of women with endometriosis. In this study, we investigated whether IL-17A could induce macrophage recruitment and M2 polarization, while promoting endometriotic lesion growth through enhanced vascularization. By utilizing a co-culture of macrophage-like THP-1 cells with an endometriotic epithelial cell line, our in vitro results suggest that IL-17A indirectly induces M2 markers CCL17 and CD206 by interacting with endometriotic epithelial cells. Further, in a syngeneic mouse model of endometriosis, IL-17A treatment increased macrophages in the peritoneum, which were also M2 in phenotype. However, IL-17A treatment did not augment proliferation or vascularization of the lesion in the study time frame. These findings suggest that IL-17A may be a stimulus inducing the pathogenic polarization of macrophages into the M2 phenotype by first acting on the endometriotic lesion itself.
Highlights
Endometriosis is a gynecological disease characterized by the growth of endometrial-like lesions in extrauterine locations, including the peritoneum, ovaries and rectovaginal pouch [1]
We used an in vitro model to test whether recombinant hIL-17A could elicit the expression of macrophage associated cytokines and chemokines as well as M1 or M2 markers in both naïve THP-1 cells and THP-1 cells differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA)
Compared to undifferentiated THP-1 cells treated with IL-17A, differentiated THP-1 cells treated with IL-17A had elevated IL-17A in the supernatant (Figure 1D), which suggests that the differentiated THP-1 cells may undergo an autocrine-induced upregulation of IL-17A production compared to the undifferentiated THP-1 monocytes
Summary
Endometriosis is a gynecological disease characterized by the growth of endometrial-like lesions in extrauterine locations, including the peritoneum, ovaries and rectovaginal pouch [1]. Subsequent interaction with peritoneal structures, combined with evasion of pelvic immunity, allows these endometrial fragments to attach, invade, establish vascularization, and develop into endometriotic foci [2, 3]. Macrophage Polarization by IL-17A in Endometriosis inflammatory condition and that the process of endometriotic lesion development is analogous to the process of wound healing. In a mouse model of endometriosis, depletion of macrophages resulted in lesions that were reduced in size and vascularity [7], suggesting that macrophages are critical for the development of endometriotic lesions. A separate study further showed that the depletion of macrophages in an endometriosis mouse model drastically reduced markers of inflammatory pain and pain sensitivity behaviors [8]
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