STUDY QUESTION: Is annexin A2 involved in the reduced phagocytic ability of macrophages in endometriosis? SUMMARY ANSWER: 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 E2 (PGE2) and this impairs the phagocytic ability of macrophages. WHAT IS ALREADY KNOWN: 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. STUDY DESIGN, SIZE, DURATION: A laboratory study. Thirty-five patients (20 with and 15 without endometriosis) of reproductive age with normal menstrual cycles were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peritoneal macrophages isolated from women with or without endometriosis were cultured and treated with vehicle, PGE2 and different EP receptor agonists, and the expression of annexin A2 was quantified by RT-PCR 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 PGE2 or cyclo-oxygenase (COX) inhibitors, and annexin A2 mRNA was quantified. MAIN RESULTS AND THE ROLE OF CHANCE: 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 PGE2 (P < 0.01/P < 0.05 in women without/with endometriosis versus control) via the EP2/EP4 receptor-dependent signaling pathway. Treatment with PGE2 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 PGE2 (P < 0.01 versus control). In contrast, treatment with COX inhibitors to inhibit PGE2 production enhanced annexin A2 expression in peritoneal macrophages (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: 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 PGE2 when compared with control subjects. WIDER IMPLICATIONS OF THE FINDINGS: Inhibiting PGE2 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. STUDY FUNDING/COMPETING INTEREST(S): 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.
STUDY QUESTION: Is annexin A2 involved in the reduced phagocytic ability of macrophages in endometriosis? SUMMARY ANSWER: 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 E2 (PGE2) and this impairs the phagocytic ability of macrophages. WHAT IS ALREADY KNOWN: 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. STUDY DESIGN, SIZE, DURATION: A laboratory study. Thirty-five patients (20 with and 15 without endometriosis) of reproductive age with normal menstrual cycles were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peritoneal macrophages isolated from women with or without endometriosis were cultured and treated with vehicle, PGE2 and different EP receptor agonists, and the expression of annexin A2 was quantified by RT-PCR 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 PGE2 or cyclo-oxygenase (COX) inhibitors, and annexin A2 mRNA was quantified. MAIN RESULTS AND THE ROLE OF CHANCE: 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 PGE2 (P < 0.01/P < 0.05 in women without/with endometriosis versus control) via the EP2/EP4 receptor-dependent signaling pathway. Treatment with PGE2 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 PGE2 (P < 0.01 versus control). In contrast, treatment with COX inhibitors to inhibit PGE2 production enhanced annexin A2 expression in peritoneal macrophages (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: 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 PGE2 when compared with control subjects. WIDER IMPLICATIONS OF THE FINDINGS: Inhibiting PGE2 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. STUDY FUNDING/COMPETING INTEREST(S): 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.
Authors: Mengfei Zhuang; Yang Cao; Yan Shi; Lin Yu; Yanan Niu; Tingting Zhang; Zhaogui Sun Journal: Evid Based Complement Alternat Med Date: 2020-05-29 Impact factor: 2.629