Pathophysiology of the Peripheral Immune Response in Acute Ischemic Stroke

Ischemic stroke triggers an inflammatory response in the affected area, which progresses for days to weeks after the onset of symptoms. The inflammatory reaction involves both tissue resident and peripheral immune cells. Thus the local inflammatory response within the ischemic territory leads to the generation of molecular cues, including cytokines, chemokines and danger-associated molecular patterns (DAMP) setting the stage for the recruitment of peripheral immune cells by weakening the blood–brain barrier (BBB) and by generating chemotactic gradients and activating signals for blood leukocytes. There is evidence that selected aspects of such inflammatory processes contribute to the progression of ischemic brain injury, worsen tissue damage, and exacerbate neurologic deficits. However, research points at a more multifaceted role of immune cells in brain ischemia, where immune cells participate in repair processes during the subacute and chronic stages of brain ischemia. In addition, the interaction of the ischemic brain and the immune system is bidirectional, and although the peripheral immune system is supplying immune cells that participate in the local inflammatory response, neural and humoral signals generated by the ischemic brain modulate the activity of the peripheral immune system leading to immunosuppression and increased risk for nosocomial infections. Understanding these processes and the nature of immune cells involved during deleterious and reparatory phases of postischemic inflammation will be necessary to devise effective therapeutic strategies for human stroke . This chapter will briefly discuss the role of peripheral immune cells participating in the inflammatory response to cerebral ischemia, deliberate potential entry points used by these cells to gain access to the ischemic tissue, and outline the role of the ischemic brain in shaping the peripheral immune response.

Cerebral Ischemia and Inflammation

Infiltration of hematogenous cells into the ischemic territory that persists for days and even weeks after the initial insult is the hallmark of the inflammatory reaction, which parallels activation of brain microglia, astrocytes, and endothelial cells. Cytokines and chemokines are important molecular cues in the inflammatory response to cerebral ischemia. The inflammatory reaction is believed to start at the time of intravascular occlusion due to altered rheology resulting in activation of the endothelium by shear stress and by activation of the coagulation cascade, which leads to the surface expression of adhesion molecules on endothelial cells, the generation of the proinflammatory proteases of the coagulation cascade (thrombin, tissue factor), and release of cytokines and lipid mediators from activated platelets [interleukin (IL)-1 and eicosanoids]. At the same time, cell injury in the ischemic territory generates DAMP including purinergic molecules and high mobility group box 1 protein that signal locally to activate brain resident immune cells but, helped by a deteriorating BBB, might also be released into the blood stream where they are sensed by circulating immune cells or can reach distant lymphoid organs such as spleen and lymph nodes, where they activate local immune cells ( Fig. 28.1 ).