Inflammation And Stroke: Is There A Link?

Inflammation is an important factor in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. The brain responds to ischemic injury with an acute and prolonged inflammatory process, characterised by rapid activation of resident cells (mainly microglia), production of proinflammatory mediators, and infiltration of various types of inflammatory cells (including neutrophils, different subtypes of T cells, monocyte/macrophages, and other cells) into the ischemic brain tissue. These cellular events collaboratively contribute to ischemic brain injury.

Chronic inflammation, or long-term inflammation, can increase the risk of having a stroke. This can be caused by poor lifestyle and dietary habits, which can lead to inflammation within the arteries, making it difficult for blood to travel properly. Additionally, inflammation can cause blockages or aneurysms in the arteries, which can result in severe consequences such as heart attack or stroke.

Inflammation in the brain after a stroke can also cause tissue that wasn't deprived of oxygen during the stroke to become permanently damaged. While acute inflammation is helpful initially after a stroke, chronic inflammation in the brain can increase the risk for other medical conditions and even a second stroke.

Inflammatory mechanisms in ischemic stroke: the role of inflammatory cells

Inflammation is a key player in the development of ischemic stroke, with various interconnected mechanisms at work. Infectious diseases, traditional risk factors, and genetic susceptibility are some of the factors that can trigger inflammatory pathways leading to stroke. While the exact causal role of these inflammatory mechanisms in stroke pathogenesis is still a subject of research, there is growing evidence of their influence.

Inflammatory cells play a dynamic and complex role in ischemic stroke, with emerging data suggesting that they can have both beneficial and adverse effects. The accumulation of inflammatory cells, particularly monocytes/macrophages, within the vascular wall is an early event during atherogenesis. In the context of ischemic stroke, various inflammatory cells, including neutrophils, different subtypes of T cells, and monocyte/macrophages, are recruited and activated. This cellular response contributes collaboratively to ischemic brain injury.

The time-dependent nature of inflammatory cell recruitment and their differential roles at various stages of ischemic stroke add to the complexity. For example, the same molecule produced by different cells, such as microglia- and leukocyte-derived TNF-α, can have distinct functions. Oxidative stress, a mediator of tissue injury in acute ischemic stroke, may serve as a common pathway for different inflammatory cells.

In addition to leukocytes, other inflammatory cells like DCs and MCs have been implicated in ischemic brain injury. DCs accumulate in the ischemic hemisphere, especially in the border region of the infarct where T cells are also present. MCs, located perivascularly in the brain, contain potent vasoactive and proteolytic substances. During ischemic stroke, ROS generated by inflammatory cells trigger the expression of proinflammatory genes, which play a role in leukocyte-endothelium interactions and secondary brain damage.

The understanding of the time-dependent recruitment and roles of inflammatory cells in ischemic stroke is crucial for developing effective therapeutic interventions. While anti-inflammatory approaches have been successful in animal models, translating these findings to human clinical applications has been challenging due to the heterogeneity of mechanisms and the uncertainty of the optimal time window for intervention.

The role of activated microglia/macrophages in cerebral I/R damage

Inflammation and infections are considered risk factors for ischemic stroke. While the final proof of a causal role of infectious or inflammatory mechanisms in stroke pathogenesis is still lacking, there is increasing evidence that inflammatory parameters are useful risk markers in routine assessments of systemic cardiovascular risk in clinical practice.

Microglia and macrophages play a significant role in the pathophysiology of the CNS. In a healthy CNS, microglia are dynamic cells that constantly scan their environment for invading pathogens or tissue damage. When they detect such signals, they initiate a pathway to resolve the injury by rapidly switching from a ramified morphology to an amoeboid one, followed by phagocytosis and the release of various mediators like pro- or anti-inflammatory cytokines. This activation of microglia and the subsequent release of pro-inflammatory cytokines can have both neuroprotective and neurotoxic effects.

Upon activation, microglia and macrophages share most phenotypical markers and effector functions. In the the context of cerebral I/R damage, CNS lesion paradigms with a breakdown of the blood-brain barrier, such as cerebral ischemia, brain abscesses, and stab wounds, prompt microglial activation, macrophage recruitment, and debris clearance.

In Alzheimer's disease, activated microglia are involved in plaque formation, and in globoid cell dystrophy, they accelerate demyelination. Additionally, in autoimmune diseases, microglia likely have dual functions, presenting antigens to T cells and exerting effector functions while also having the capacity to downregulate T cell responses.

The role of activated microglia and macrophages in cerebral I/R damage is complex, and further research is needed to fully understand their impact on stroke risk and pathophysiology.

The role of neutrophil infiltration in cerebral I/R damage

Inflammation is a key factor in stroke susceptibility and outcome. Cerebral I/R injury is associated with the activation of inflammatory cells, including neutrophils, T cells, and monocytes/macrophages. Neutrophils are the first blood-derived immune cells to invade ischemic tissue, and their infiltration plays a detrimental role in ischemic tissue damage.

Neutrophil infiltration in cerebral I/R damage is an early and significant event, marked by the activation of endothelial cells and the expression of chemokines and adhesion molecules. This process further aggravates cerebral ischemic injury. Infiltrating neutrophils release oxygen free radicals, proteases, and pro-inflammatory cytokines, which contribute to inflammatory damage. Additionally, neutrophils cause secondary injury by releasing pro-inflammatory factors, ROS, proteases, and matrix metalloproteinases (MMPs). These factors damage the endothelial cell membrane and basal layer, leading to changes in BBB permeability and edema after ischemia.

The complex role of neutrophils in cerebral I/R damage is further highlighted in the context of cerebral ischaemia and neuronal death. While circulating neutrophils may not be significant contributors, the presence of cerebral infiltrating neutrophils is strongly associated with haemorrhagic complications. Specifically, the numbers of infiltrating neutrophils correlate with these complications through MMP-9.

Targeting neutrophil infiltration has been proposed as a potential therapeutic strategy for cerebral ischemia. For instance, CXCR2 blockade, which prevents neutrophil recruitment into the brain, has been suggested as an effective treatment option for stroke patients with hyperlipidemia. However, it is important to note that the success of anti-inflammatory approaches in animal models has not yet translated into clinical applications due to the heterogeneity in mechanisms underlying post-ischemic brain inflammation and the uncertainty in timing.

The role of different subtypes of T lymphocytes in cerebral I/R damage

T cells are a type of white blood cell that play a central role in the adaptive immune response. They are born in the bone marrow and mature in the thymus gland. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface. T cells can be divided into two major subtypes: CD4+ "helper" T cells and CD8+ "killer" T cells. Helper T cells assist other lymphocytes, while killer T cells are able to directly kill virus-infected cells, as well as cancer cells. T cells can be further divided into several subsets, such as regulatory T cells, which have an important role in the maintenance of immunological tolerance.

The role of other inflammatory cells in cerebral I/R damage

Inflammation is a key component of the immune system's response to harmful stimuli, such as pathogens, damaged cells, and toxic compounds. Inflammatory responses can be triggered by a variety of factors, including infection, traumatic brain injury, toxic compounds, or autoimmunity. The inflammatory response is the coordinated activation of signalling pathways that regulate inflammatory mediator levels in resident tissue cells and inflammatory cells recruited from the blood.

The inflammatory response involves a highly coordinated network of many cell types, including neutrophils, monocytes, macrophages, T cells, B cells, and mast cells.

Inflammation is a common pathogenesis of many chronic diseases, including cardiovascular and bowel diseases, diabetes, arthritis, and cancer. Inflammatory responses occur in the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system, potentially leading to tissue damage or disease.

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