Intravital correlated microscopy reveals differential macrophage and microglial dynamics during resolution of neuroinflammation.

Tjakko J Van Ham,Klaas A Sjollema,Anneke Veenstra-Algra,Nynke Oosterhof,Colleen A Brady,Jeroen Kuipers,Ben N G Giepmans,Ruby D Kalicharan,Harm H Kampinga,Randall T Peterson

doi:10.1242/dmm.014886

Tjakko J Van Ham, Klaas A Sjollema + Show 8 more

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https://doi.org/10.1242/dmm.014886

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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.

Highlights

In the vertebrate brain, immune cells including microglia can play both beneficial and detrimental roles in response to, for example, traumatic injury, stroke or neurodegenerative disease (Dirnagl et al, 1999; Shechter and Schwartz, 2013a; Sokolowski and Mandell, 2011)
Here, the authors use intravital microscopy of cellular interactions in living zebrafish brain and electron microscopy to provide new insights into the immune response to brain injury, and to determine how neuroinflammation is stopped in vivo
They show that peripheral macrophages and resident microglia are both involved in clearing dying cells. They use electron microscopy to provide an unprecedented view of the cellular and ultrastructural features associated with neuronal ablation and the subsequent immune responses. They show that the timing of macrophage and microglia involvement is different, with macrophages being present at early stages whereas microglia dominate several days after the ablation

Summary

Introduction

Immune cells including microglia can play both beneficial and detrimental roles in response to, for example, traumatic injury, stroke or neurodegenerative disease (Dirnagl et al, 1999; Shechter and Schwartz, 2013a; Sokolowski and Mandell, 2011). A supportive function can be mediated by clearing dead cells and debris, and possibly disease-related products such as protein. Received 14 November 2013; Accepted 29 April 2014 aggregates (London et al, 2013; Mildner et al, 2011; Shechter and Schwartz, 2013b; Sokolowski and Mandell, 2011) Such a protective function of immune cells might be lost due to aging and could thereby contribute to, for example, Alzheimer’s disease (Streit et al, 2009). Following brain damage it remains unclear which immune cells are recruited under what circumstances; how these immune cells disappear again; and how resolution of neuroinflammation is achieved (Schwartz and Baruch, 2014)

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