Population control of resident and immigrant microglia by mitosis and apoptosis.
Microglial population expansion occurs in response to neural damage via processes that involve mitosis and immigration of bone marrow-derived cells. However, little is known of the mechanisms that regulate clearance of reactive microglia, when microgliosis diminishes days to weeks later. We have investigated the mechanisms of microglial population control in a well-defined model of reactive microgliosis in the mouse dentate gyrus after perforant pathway axonal lesion. Unbiased stereological methods and flow cytometry demonstrate significant lesion-induced increases in microglial numbers. Reactive microglia often occurred in clusters, some having recently incorporated bromodeoxyuridine, showing that proliferation had occurred. Annexin V labeling and staining for activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling showed that apoptotic mechanisms participate in dissolution of the microglial response. Using bone marrow chimeric mice, we found that the lesion-induced proliferative capacity of resident microglia superseded that of immigrant microglia, whereas lesion-induced kinetics of apoptosis were comparable. Microglial numbers and responses were severely reduced in bone marrow chimeric mice. These results broaden our understanding of the microglial response to neural damage by demonstrating that simultaneously occurring mitosis and apoptosis regulate expansion and reduction of both resident and immigrant microglial cell populations.
Wirenfeldt
Martin
M
Medical Biotechnology Center, Institute of Medical Biology, University of Southern Denmark, Odense, Denmark. mwirenfeldt@gmail.com
Dissing-Olesen
Lasse
L
Anne Babcock
Alicia
A
Nielsen
Marianne
M
Meldgaard
Michael
M
Zimmer
Jens
J
Azcoitia
Iñigo
I
Leslie
Robert Graham Quinton
RG
Dagnaes-Hansen
Frederik
F
Finsen
Bente
B
D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000379:methods; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism
D039481:CD11b Antigen; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor