title: Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance.
abstract: The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor(-/-) mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Bangwei
authors.initials: B
authors.lastname: Luo
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Woting
authors.initials: W
authors.lastname: Gan
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Rongchen
authors.initials: R
authors.lastname: Shi
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China.
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China. Electronic address: zhangzhiren@yahoo.com.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, 30 Gaotanyan Main Street, Chongqing 400038, China. Electronic address: wuyuzhang@yahoo.com.
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication; D010587:Phagocytosis / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D047495:PPAR gamma; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; C060506:sphingosine 1-phosphate; D013110:Sphingosine