Immune responses to stroke: mechanisms, modulation, and therapeutic potential

Abstract

Stroke is the second leading cause of death worldwide and a leading cause of disability. Most strokes are caused by occlusion of a major cerebral artery, and substantial advances have been made in elucidating how ischemia damages the brain. In particular, increasing evidence points to a double-edged role of the immune system in stroke pathophysiology. In the acute phase, innate immune cells invade brain and meninges and contribute to ischemic damage, but may also be protective. At the same time, danger signals released into the circulation by damaged brain cells lead to activation of systemic immunity, followed by profound immunodepression that promotes life-threatening infections. In the chronic phase, antigen presentation initiates an adaptive immune response targeted to the brain, which may underlie neuropsychiatric sequelae, a considerable cause of poststroke morbidity. Here, we briefly review these pathogenic processes and assess the potential therapeutic value of targeting immunity in human stroke.

Figure 1. Cerebral and systemic immune changes in acute stroke: innate immunity.

(A) After ischemia, circulating white cells stick to the cerebral endothelium and extravasate into the brain and meninges. Recent evidence implicates the skull bone marrow as a source of meningeal inflammatory cells (101). Cerebral ischemia also damages brain cells, which release DAMPs. DAMPs activate innate immune receptors on microglia and other cells, leading to the release of cytokines and chemokines, which, in turn, promote additional neutrophil entry. Neutrophils damage the brain by producing ROS, metalloproteases (MMPs), perforins, cytokines, and neutrophil extracellular traps (NETs). Activation of the complement cascade (Cmp) also damages brain cells. (B) Brain damage triggers a neurohumoral response (via the hypothalamic-hypophyseal axis and autonomic nervous system), which leads to activation of the adrenal glands and secretion of glucocorticoids and catecholamines. Brain-derived DAMPs leak into the circulation and activate systemic immunity, mobilizing innate immune cells form lymphoid organs and the gut. The increase in gut permeability may release bacteria and their metabolites into the circulation. (C) DAMPs activate systemic immunity through pattern recognition receptors, including TLRs and RAGE, on immune cells. This activation phase is followed by immunodepression, attributable mainly to the systemic effects of β-adrenoreceptors, which increases the propensity to post-stroke infections.

Figure 2. Cerebral and systemic immune changes in the chronic phase of stroke: adaptive immunity.

(A) With tissue damage, dead cells release new antigens that may enter into contact with antigen presenting cells (APCs) in the brain. (B) Although not firmly established, these cells may enter the circulation and home into peripheral lymphoid organs. At the same time, antigens also reach the circulation and are detected by APCs in lymphoid organs. APCs, in turn, engage naive lymphocytes, which undergo differentiation (T or B cells) and clonal expansion, and reenter the circulation. These “autoreactive” lymphocytes, sensitized against brain antigens, home back into the brain and cause chronic inflammation and cytotoxicity, which may underlie the chronic sequelae of stroke.

Figure 3. Timing and success of selected immunomodulatory therapies for stroke.

Human studies were selected as those that were later stage and utilized immunomodulatory drugs or antibodies. For each agent, the human studies are listed in chronological order, with the length of the bars indicating the treatment period from the time the participant was last seen normal. Below the human trials are animal studies with that agent where the first dose was delivered after stroke, and either infarct size or neurological outcome was tested. If both were positive, the animal studies are marked with a circle, and if both were negative, they are marked with an x. In cases where only neurological outcome or only stroke size was tested, or where one was positive and the other negative, the study is not marked with a symbol. Comorbidities in animal studies were aging, diabetes, hypertension, and hypercholesterolemia. Additional details and references are in Supplemental Table 1. *This study had a positive effect in males but not females. **Drug dose timing listed only as mean ± SD, which is graphed here.