Ischemia, Immunosuppression and Infection--Tackling the Predicaments of Post-Stroke Complications

Abstract

The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the most common medical complication in stroke patients is infection. In fact, infections, such as pneumonia and urinary tract infections, greatly worsen the clinical outcome of stroke patients. Recent evidence suggests that the disrupted interplay between the central nervous system and immune system contributes to the development of infection after stroke. The suppression of systemic immunity by the nervous system is thought to protect the brain from further inflammatory insult, yet this comes at the cost of increased susceptibility to infection after stroke. To improve patient outcome, there have been attempts to lessen the stroke-associated bacterial burden through the prophylactic use of broad-spectrum antibiotics. However, preventative antibiotic treatments have been unsuccessful, and therefore have been discouraged. Additionally, with the ever-rising obstacle of antibiotic-resistance, future therapeutic options to reverse immune impairment after stroke by augmentation of host immunity may be a viable alternative option. However, cautionary steps are required to ensure that collateral ischemic damage caused by cerebral inflammation remains minimal.

Keywords: antibiotics; clinical outcome; immunosuppression; infection; stroke.

Figure 1

Immunological processes and mechanisms for infection after stroke. During a stroke, interrupted blood flow into the brain deprive cells of vital nutrients and thus undergo cell death. This in turn activates local immune cells to produce pro-inflammatory factors, which can have deleterious effects on the brain. Additionally, restoration of blood flow into the brain allows for reperfusion, resulting in ROS production and BBB breakdown. This allows for excessive recruitment and infiltration of circulating immune cells into the brain to promote swelling and increased intracranial pressure to exacerbate brain damage. In an attempt to reduce damage and resolve local inflammation, the brain responds by activating the SNS and HPA-axis in order to produce catecholamines and glucocorticoids. Catecholamines and glucocorticoids can act upon iNKT cells and T cells, respectively. Meanwhile, APC and neutrophils are also impaired to the paint where their bactericidal activities are insufficient, all of which resulting in systemic immune suppression and therefore leaving stroke sufferers more susceptible to infections. The brain and stroke are represented by a cloud and a bolt, respectively. Arrows denote “activate” or “induce”; blunted arrows denote “inhibit” or “prevent”. Dashed lines denote activities locally in the brain versus systemically in the periphery.