title: Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo.
abstract: Alternatively activated macrophages (M2) regulate immune responses and ex vivo polarized splenic M2 are able to ameliorate renal injury including models of renal disease, such as adriamycin nephropathy. Whether M2 derived from other organs have similar protective efficacy is unknown. Here, we report adoptively transferred bone marrow M2 macrophages did not improve renal function or reduce renal injury in adriamycin nephropathy, whereas splenic M2 macrophages were protective. Bone marrow and splenic M2 macrophages showed similar regulatory phenotypes and suppressive functions in vitro. Within the inflamed kidney, suppressive phenotypes in bone marrow but not in splenic M2 macrophages, were dramatically reduced. Loss of the suppressive phenotype in bone marrow M2 was related to strong proliferation of bone marrow M2. Bone marrow M2 proliferation in vivo correlated with M-CSF expression by tubular cells in the inflamed kidney. Inhibition of M-CSF in vitro limited bone marrow M2 proliferation and prevented switch of phenotype. Proliferating cells derived from transfused bone marrow M2 were inflammatory rather than regulatory in their phenotype and function. Thus bone marrow in contrast to splenic M2 macrophages do not protect against renal structural and functional injury in murine adriamycin nephropathy. The failed renoprotection of bone marrow M2 is due to the switch of transfused M2 macrophages from a regulatory to an inflammatory phenotype.
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Dong
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Changqi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Flow Cytometry Facility, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Lee
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Thian K
authors.initials: TK
authors.lastname: Tan
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Yuan M
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David C H
authors.initials: DC
authors.lastname: Harris
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D004317:Doxorubicin; D007674:Kidney Diseases / Q000139:chemically induced / Q000628:therapy*; D007684:Kidney Tubules / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D008297:Male; D008807:Mice, Inbred BALB C; D010641:Phenotype; D013154:Spleen / Q000276:immunology*
chemical_list: D004317:Doxorubicin; D016173:Macrophage Colony-Stimulating Factor