br Conflict of interest br
Conflict of interest
Introduction Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus, most often in the pelvic peritoneum and ovaries. This disorder affects an estimated 10% of women in the reproductive age group and is basically an estrogen-dependent benign gynecological disease. Repeated episodes of retrograde menstruation or ovarian hemorrhage occur in the peritoneal cavity or ovarian endometrioma (OE), respectively . Endometriosis results in a local accumulation of hemoglobin, heme and iron species, which causes severe oxidative stress and antioxidants depletion, leading to distortion in the redox balance . Altered homeostatic redox balance of the environment may support chronic inflammation, uncontrolled proliferation and then malignant transformation . Actually, endometriosis increases the subsequent risk of developing endometriosis-associated ovarian cancer (EAOC) [3,4]. Endometriotic lesions are highly infiltrated with various leukocytes, including macrophages that secrete antioxidants and immunosuppressive factors [1,, , ]. Endometriosis infiltrating macrophages might adapt to these stressful environmental conditions by secreting antioxidants that control excess oxidative stress . Oxidative stress and Paeonol in the surrounding environment contribute to several aspects of macrophage functions including recruitment, activation and the shift in cell polarity. Macrophage polarization may have a distinct role in the inflammatory, immune and neoplastic diseases [8,9]. Macrophages are classified into the pro-inflammatory, classically activated M1 macrophages that possess antitumor activity and the alternatively activated M2 macrophages that support tumor progression and malignancy [8,9]. For the phenotypical characterization of infiltrating macrophages, immunohistochemistry employing selected literature-based prototype-antibodies against CD11c, CD163 and CD68 was evaluated in this study. Although CD11c is a specific marker in macrophages and dendritic cells , CD11c-based immunohistochemistry is used as a M1 phenotype specific marker [11,12]. CD11c, a member of integrin family, induces tissue injury and the inflammatory response . The protein expression of M2 phenotype specific marker CD163 is tested via immunohistochemistry. CD163 is a hemoglobin/haptoglobin scavenger receptor and acts to protect tissues from oxidative damage . CD68 is specifically expressed by tissue macrophages and used as a pan-macrophages marker . When the microenvironment is altered in endometriosis by an excess oxidative stress and inflammatory insult, knowledge on how macrophages respond to its changes is limited. An antioxidant enzyme, heme oxygenase-1 (HO-1), is a key mediator that allows the resolution of inflammatory processes [15,16]. HO-1 is responsible for the catabolism of heme to carbon monoxide (CO), biliverdin, and iron. HO-1 was poorly expressed in peritoneal mesothelium and macrophages, but highly expressed in endometriotic lesions .
Materials and methods
Discussion First, we found that CD163+ M2-like cells were outnumbered by CD11c+ M1-like cells in the two groups. M1 macrophages secrete inflammatory cytokines and contribute to the adaptive immune response through Th1 responses [8,18]. In contrast, anti-inflammatory M2 macrophages induce Th 2 responses and tissue repair [8,18]. Environmental stimuli shape macrophage plasticity in the OE and EAOC groups, and modify macrophages phenotypes from an anti-tumor M1 type to a pro-tumor M2 type [8,, , ]. It has been established that CD163 is classified into the marker of alternatively activated M2 phenotype and acts as a hemoglobin scavenger receptor on macrophage . The possible role of macrophages in carcinogenesis has not been directly examined between the OE and its malignant transformation. However, our data support the finding that endometriosis environment itself has a propensity to develop into ovarian cancer.