The Role of Monocytes in Ischemic Stroke Pathobiology: New Avenues to Explore

Someplace in here a smart person could figure out what further research is needed to make something useful out of this. But since we don't have anyone in our stroke associations with two functioning neurons the answers will not be coming from there.

The Role of Monocytes in Ischemic Stroke Pathobiology: New Avenues to Explore

Ayman ElAli^1,2* and Noëmie Jean LeBlanc²

• ¹Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec City, QC, Canada
• ²Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Québec City, QC, Canada

Ischemic stroke accounts for the majority of stroke cases and constitutes a major cause of death and disability in the industrialized world. Inflammation has been reported to constitute a major component of ischemic stroke pathobiology. In the acute phase of ischemic stroke, microglia, the resident macrophages of the brain, are activated, followed by several infiltration waves of different circulating immune cells into the brain. Among these circulating immune cells, monocytes have been shown to play a particularly important role. Following their infiltration, monocytes differentiate into potent phagocytic cells, the monocyte-derived macrophages (MDMs), in the ischemic brain. Initially, the presence of these cells was considered as marker of an exacerbated inflammatory response that contributes to brain damage. However, the recent reports are suggesting a more complex and multiphasic roles of these cells in ischemic stroke pathobiology. Monocytes constitute a heterogeneous group of cells, which comprises two major subsets in rodent and three major subsets in human. In both species, two equivalent subsets exist, the pro-inflammatory subset and the anti-inflammatory subset. Recent data have demonstrated that ischemic stroke differentially regulate monocyte subsets, which directly affect ischemic stroke pathobiology and may have direct implications in ischemic stroke therapies. Here, we review the recent findings that addressed the role of different monocyte subsets in ischemic stroke pathobiology, and the implications on therapies.

Introduction

Stroke is the third leading cause of death and the first cause of disability in industrialized world. Ischemic stroke accounts for the majority of stroke cases, whereas the remaining stroke cases are hemorrhagic (Dirnagl et al., 1999). Regional blood supply disruption initiates the ischemic cascade that leads to neuronal death and rapid loss of neuronal function (Dirnagl et al., 1999). The ischemic cascade is characterized by the activation of several signaling pathways that compromise cell survival and function (Mehta et al., 2007). Ischemic stroke triggers blood-brain barrier (BBB) breakdown, thus contributing to the secondary progression of ischemic injury by increasing brain edema and exacerbating the inflammatory response in the sub-acute phase (hours to days after ischemic stroke onset; Dirnagl et al., 1999; Fagan et al., 2004). The severity of these early events reduces the capacity of neurons to recover in the chronic phase (days to weeks after ischemic stroke onset), thus significantly worsening stroke outcomes (Moskowitz et al., 2010).

Inflammation plays a central role in ischemic stroke pathobiology (Jin et al., 2010). Following ischemic stroke, microglia, which are brain resident macrophages, are activated and circulating immune cells, such as monocytes, neutrophils and lymphocytes are recruited to injury site (Jin et al., 2010). Among these immune cells, monocytes that give rise to macrophages play a particularly important role (Chiba and Umegaki, 2013). Initially, the presence of monocytes at the injury site has been suggested to contribute to ischemic injury exacerbation in the acute phase (minutes to hours after ischemic stroke onset; Chen et al., 2003). However, the experimental approaches that aimed at depleting these cells in ischemic stroke animal models worsened ischemic injury by destabilizing brain microvasculature (Gliem et al., 2012). These reports outline the complex and multifaceted role of monocytes in ischemic stroke pathobiology. As such, this mini-review aims to summarize and discuss the recent findings that addressed the role of different monocyte subsets in ischemic stroke pathobiology, which may have direct implication on stroke therapies.