Suppression of annexin A2 by prostaglandin E2 impairs phagocytic ability of peritoneal macrophages in women with endometriosis

Is annexin A2 involved in the reduced phagocytic ability of macrophages in endometriosis? Data from women with endometriosis and a murine model of the disease show that expression of annexin A2 in peritoneal macrophages is inhibited by prostaglandin E-2 (PGE(2)) and this impairs the phagocytic ability of macrophages. Endometriosis is a chronic inflammatory disease that recruits many immune cells, especially macrophages, to the peritoneal cavity. The phagocytic ability of peritoneal macrophages isolated from women with endometriosis is reduced. A laboratory study. Thirty-five patients (20 with and 15 without endometriosis) of reproductive age with normal menstrual cycles were recruited. Peritoneal macrophages isolated from women with or without endometriosis were cultured and treated with vehicle, PGE(2) and different EP receptor agonists, and the expression of annexin A2 was quantified by RTPCR and western blotting. Annexin A2 was knocked down (by small interfering RNA) in normal macrophages or overexpressed (by treatment with recombinant protein) in endometriotic macrophages and their phagocytic ability was measured by flow cytometry. Peritoneal macrophages were isolated from a mouse model of endometriosis and treated with PGE(2) or cyclo-oxygenase (COX) inhibitors, and annexin A2 mRNA was quantified. Levels of annexin A2 were markedly reduced in peritoneal macrophages from women with endometriosis versus controls (mRNA: P 0.01). The level of annexin A2 mRNA in the macrophages was reduced by PGE(2) (P 0.01/P 0.05 in women without/with endometriosis versus control) via the EP2/EP4 receptor-dependent signaling pathway. Treatment with PGE(2) or knockdown of annexin A2 inhibited the phagocytic ability of macrophages (P 0.05 versus control), while treatment with annexin A2 recombinant protein enhanced phagocytosis. Autologous transplantation animal studies further confirmed that levels of annexin A2 in peritoneal macrophages were markedly reduced in mice treated with PGE(2) (P 0.01 versus control). In contrast, treatment with COX inhibitors to inhibit PGE(2) production enhanced annexin A2 expression in peritoneal macrophages (P 0.05 versus control). We have provided no direct demonstration that phagocytic activity is indeed decreased in peritoneal cells from patients with endometriosis or that their endometriotic fluid contains increased amounts of PGE(2) when compared with control subjects. Inhibiting PGE(2) signaling, in order to restore or enhance the phagocytic capability of macrophages, may represent a new direction of thinking in developing novel strategies against endometriosis. This work was supported by grants from National Science Council of Taiwan, Republic of China (NSC97-2314-B-006-020-MY3) to M.-H.W. and (NSC98-2320-B-006-026-MY3) to S.-J.T., and grants from the Chang Gung Memorial Hospital, Taiwan, Republic of China (CMRPG891432 and CMRPG8A0531) to P.-C.C. None of the authors have any conflicts of interest.