title: Intravital correlated microscopy reveals differential macrophage and microglial dynamics during resolution of neuroinflammation.
abstract: Many brain diseases involve activation of resident and peripheral immune cells to clear damaged and dying neurons. Which immune cells respond in what way to cues related to brain disease, however, remains poorly understood. To elucidate these in vivo immunological events in response to brain cell death we used genetically targeted cell ablation in zebrafish. Using intravital microscopy and large-scale electron microscopy, we defined the kinetics and nature of immune responses immediately following injury. Initially, clearance of dead cells occurs by mononuclear phagocytes, including resident microglia and macrophages of peripheral origin, whereas amoeboid microglia are exclusively involved at a later stage. Granulocytes, on the other hand, do not migrate towards the injury. Remarkably, following clearance, phagocyte numbers decrease, partly by phagocyte cell death and subsequent engulfment of phagocyte corpses by microglia. Here, we identify differential temporal involvement of microglia and peripheral macrophages in clearance of dead cells in the brain, revealing the chronological sequence of events in neuroinflammatory resolution. Remarkably, recruited phagocytes undergo cell death and are engulfed by microglia. Because adult zebrafish treated at the larval stage lack signs of pathology, it is likely that this mode of resolving immune responses in brain contributes to full tissue recovery. Therefore, these findings suggest that control of such immune cell behavior could benefit recovery from neuronal damage.
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. T.vanHam@ErasmusMC.nl.
authors: Tjakko J
authors: TJ
authors: van Ham
authors: Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors: Colleen A
authors: CA
authors: Brady
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Ruby D
authors: RD
authors: Kalicharan
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Nynke
authors: N
authors: Oosterhof
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Jeroen
authors: J
authors: Kuipers
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Anneke
authors: A
authors: Veenstra-Algra
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Klaas A
authors: KA
authors: Sjollema
authors: Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors: Randall T
authors: RT
authors: Peterson
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Harm H
authors: HH
authors: Kampinga
authors: Department of Cell Biology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors: Ben N G
authors: BN
authors: Giepmans
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D002452:Cell Count; D016923:Cell Death; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D007814:Larva; D008264:Macrophages / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology* / Q000648:ultrastructure; D008853:Microscopy / Q000379:methods*; D009474:Neurons / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D010586:Phagocytes / Q000473:pathology / Q000648:ultrastructure; D010587:Phagocytosis; D013997:Time Factors; D015027:Zebrafish
chemical_list: D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C026742:plastin; D049452:Green Fluorescent Proteins
keywords: Brain; Intravital microscopy; Leukocytes; Microglia; Neurodegeneration; Zebrafish