Brain inflammation after stroke

Abstract

Stroke is a leading cause of mortality and disability worldwide. However, current treatment for stroke has limitations in therapeutic benefit and window of opportunity. There is an urgent need for development of novel therapies that can limit brain injury and/or promote protection and repair following stroke. The process of brain inflammation that occurs subsequent to the initial ischemic insult appears to promote secondary brain injury and has thus been identified as a potential therapeutic target in stroke. This thesis provides novel insights on the mechanisms and contributions of post-ischemic inflammation in the brain after stroke, using a mouse model of ischemia with or without reperfusion. In Chapter 3 the work quantified different immune cell infiltration into the brain at an early (3 h) and late (24 h) timepoint after permanent cerebral ischemia and compared the profile with that of transient ischemia (1 h or 2 h) followed by 22 h or 23 h of reperfusion. Different immune cells displayed distinct temporal profiles of infiltration after stroke. Moreover, compared with permanent ischemia, there were ~50% fewer infiltrating leukocytes at 24 h after ischemia-reperfusion, independent of infarct size. These findings indicate that a profound infiltration of inflammatory cells occurs in the brain early after focal ischemia, especially without reperfusion. In Chapter 4 the work assessed the effect of Ly6Chi monocytes recruited into the brain early after ischemic stroke, using a selective CC chemokine receptor 2 (CCR2) antagonist, INCB3344. This treatment effectively reduced circulating levels of monocytes as well as monocyte infiltration into the brain after ischemia-reperfusion. The data suggest that Ly6Chi monocytes exert an acute protective effect after transient cerebral ischemia to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization. In Chapter 5 the work assessed the effect of CCR2 inhibition during permanent cerebral ischemia. Findings indicated that the increase in circulating bone marrow-derived Ly6Chi monocytes, but not the infiltration of those cells into the brain, was blocked by the CCR2 antagonist. Furthermore, INCB3344 had no effect on either neurological deficit or infarct volume after permanent cerebral ischemia. The data confirm that cerebral ischemia triggers a CCR2-dependent increase in circulating Ly6Chi monocytes but suggests that, in the absence of reperfusion, these cells may transmigrate into the ischemic brain in a CCR2-independent manner. In Chapter 6 the work examined the effect of two major B cell subpopulations, B2 and B1a cells, on stroke outcome after transient cerebral ischemia. The studies found that both total B cell depletion and selective B1a depletion worsened stroke outcome while B2 deficiency (BAFFR-/-) had no effect on stroke outcome. The results suggest that the B1a subpopulation, which represents <1 % of the total B cells in the circulation, may play a significant role in modulating brain injury after stroke, possibly via a mechanism involving immunoglobulin-mediated neuroprotection. Collectively, these findings provide novel insights into the acute inflammatory mechanisms in the brain after ischemic stroke and reveal potential therapeutic targets that may be exploited to modulate components of the immune system for the treatment of stroke.