The double‐edged sword of inflammation after stroke: What sharpens each edge?

In this issue of Annals of Neurology, we get an example of the old adage that inflammation after stroke is a double-edged sword, with a focus on the role of peripheral macrophages. However, we also get the added nuance that depending on the inflammatory state of the individual, one edge of the sword may be sharper than the other. In the article by Michael Gliem and his colleagues a new beneficial aspect of post stroke inflammation is identified. Gliem and his colleagues show that the infiltration of CCR2-expressing monocytes from the periphery, and their differentiation into macrophages, plays a beneficial role in preventing hemorrhagic transformation after stroke. The removal of these cells did not reduce infarct size, suggesting that they do not contribute substantially to aggravating stroke pathophysiology, if indeed they do at all. This is an important and exciting contribution to the field that helps us to dissect the role of an individual component of the inflammatory response to stroke. However, this study was conducted in healthy young mice. In contrast to the Gliem et al paper, this issue also contains a paper by Eunhee Kim and coworkers that demonstrates a negative effect of inflammation after stroke. Kim and coworkers show that CD36-expressing immune cells in the periphery, which include CCR2expressing monocytes, but also dendritic cells, B cells, and platelets, play a detrimental role after stroke by increasing lesion size. However, this study was conducted in a mouse model of hyperlipidemia, a common comorbidity in stroke patients. These findings hint at CCR2-expressing monocytes performing a double-dealing role after stroke, depending on the inflammatory milieu of the organism. On the one hand in Gliem et al they appear to be prevailingly beneficial, aiding the repair process, but in Kim et al they appear to contribute to secondary ischemic injury. One way of rationalizing these discordant findings is that the CD36-positive cells that contribute to injury in Kim et al may not be CCR2-positive monocytes, but instead one of the other cell types in the periphery that express CD36. However, this is unlikely, because Kim et al find that most CD36 expression in the brain after stroke is from bone marrow-derived cells and peaks at 72 hours, which is the same time as peak infiltration of CCR2expressing monocytes. An alternative way of explaining these findings is that in the context of underlying systemic inflammation, such as that caused by hyperlipidemia, the monocyte response to stroke may be primed to have a more negative impact (Fig 1). Indeed this is supported by work by Barry McColl et al, who have shown that both an acute and chronic proinflammatory stimulus worsen stroke outcome. The finding by Muhammad et al that infection with influenza virus a few days before stroke also worsens stroke outcome further supports this. The mechanism by which underlying inflammation makes stroke more injurious may be by altering the balance of classic versus alternatively activated macrophages. Classically activated macrophages mediate chronic inflammation and promote tissue injury, whereas alternatively activated macrophages tend to resolve inflammation and facilitate wound healing. Hyperlipidemia and other stroke comorbidities may cause more macrophages to adopt the classically activated phenotype, leading to greater release of proinflammatory cytokines after stroke and greater injury to the brain microvasculature. Intriguingly, in the study by Kim et al, although hyperlipidemic mice lacking CD36-expressing immune cells in the periphery had a smaller lesion size, their survival rate was reduced from 94% to 73%. Using Fisher’s exact test, this reduction does not reach significance (p 1⁄4 0.1); however, one cannot help but wonder if these mice had an increased incidence of hemorrhagic transformation. If they did, it would bring the findings of both papers into elegant alignment. Gliem and colleagues used pharmacological and chimeric approaches to demonstrate that CCR2-expressing monocytes infiltrate the brain after stroke and transform into noninflammatory phagocytes. They show that this early recruitment of monocytes into the brain is an essential prerequisite for stabilization of the neurovascular unit through a transforming growth factor (TGF) b1-dependent mechanism, and that this repair function outweighs any transient detrimental action that the cells may have. This finding adds to the growing body of literature suggesting that TGFb1 induction after stroke is part of a repair process that tightly regulates the entry of peripheral monocytes/macrophages across an intact blood–brain barrier.