One of the leading causes of neurological mortality, disability, and dementia worldwide is cerebral ischemia. Among the many pathological phenomena, the immune system plays an important role in the development of post-ischemic degeneration of the brain, leading to the development of neuroinflammatory changes in the brain. After cerebral ischemia, the developing neuroinflammation causes additional damage to the brain cells, but on the other hand it also plays a beneficial role in repair activities. Inflammatory mediators are sources of signals that stimulate cells in the brain and promote penetration, e.g., T lymphocytes, monocytes, platelets, macrophages, leukocytes, and neutrophils from systemic circulation to the brain ischemic area, and this phenomenon contributes to further irreversible ischemic brain damage. In this review, we focus on the issues related to the neuroinflammation that occurs in the brain tissue after ischemia, with particular emphasis on ischemic stroke and its potential treatment strategies.

Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells, facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells may accumulate in the capillaries, further impairing cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, may release pro-inflammatory mediators, such as cytokines, chemokines and oxygen/nitrogen free radicals that contribute to the evolution of tissue damage. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1beta. The present work reviewed the role of neuroinflammatory mediators in the pathophysiology of ischemic brain damage and their potential exploitation as drug targets for the treatment of cerebral ischemia.

Local and systemic inflammation contribute significantly to stroke risk factors as well as determining stroke impact and outcome. Previously being considered as an immuno-privileged domain, the central nervous system is now recognized for multiple and complex interactions with the immune system in health and disease. The sterile inflammatory response emerging after ischemic stroke is a major pathophysiological hallmark and considered to be a promising therapeutic target. Even (mal)adaptive immune responses following stroke, potentially contributing to long-term impact and outcome, are increasingly discussed. However, the complex interaction between the central nervous and the immune system are only partially understood, placing neuroimmunological investigations at the forefront of preclinical and clinical research. This Focused Update summarizes current knowledge in stroke neuroimmunology across all relevant disciplines and discusses major advances as well as recent mechanistic insights. Specifically, neuroimmunological processes and neuroinflammation following ischemic are discussed in the context of blood-brain barrier dysfunction, microglia activation, thromboinflammation, and sex differences in poststroke neuroimmunological responses. The Focused Update further highlights advances in neuroimaging and experimental treatments to visualize and counter neuroinflammatory consequences of ischemic stroke.

Translational stroke research has long been focusing on neuroprotective strategies to prevent secondary tissue injury and promote recovery after acute ischemic brain injury. The inflammatory response to stroke has more recently emerged as a key pathophysiological pathway contributing to stroke outcome. It is now accepted that the inflammatory response is functionally involved in all phases of the ischemic stroke pathophysiology. The immune response is therefore considered a breakthrough target for ischemic stroke treatment. On one side, stroke induces a local neuroinflammatory response, in which the inflammatory activation of glial, endothelial and brain-invading cells contributes to lesion progression after stroke. On the other side, ischemic brain injury perturbs systemic immune homeostasis and results in long-lasting changes of systemic immunity. Here, we briefly summarize current concepts in local neuroinflammation and the systemic immune responses after stroke, and highlight two promising therapeutic strategies for poststroke inflammation.

Immunological mechanisms have come into the focus of current translational stroke research, and the modulation of neuroinflammatory pathways has been identified as a promising therapeutic approach to protect the ischemic brain. However, stroke not only induces a local neuroinflammatory response but also has a profound impact on systemic immunity. In this review, we will summarize the consequences of ischemic stroke on systemic immunity at all stages of the disease, from onset to long-term outcome, and discuss underlying mechanisms of systemic brain-immune communication. Furthermore, since stroke commonly occurs in patients with multiple comorbidities, we will also overview the current understanding of the potential role of systemic immunity in common stroke-related comorbidities, such as cardiac dysfunction, atherosclerosis, diabetes, and infections. Finally, we will highlight how targeting systemic immunity after stroke could improve long-term outcomes and alleviate comorbidities of stroke patients.

After injury, activation and recruitment of inflammatory and immune cells has been thought to occur throughout the whole body. A recent study shows that after brain injury in mice, immune cells are primarily recruited from nearby skull bone marrow and invade the brain through microscopic vascular channels. Manipulation of this process may provide new therapeutic options.

Cerebral ischemia is caused by arterial occlusion due to a thrombus or an embolus. Such occlusion induces multiple and concomitant pathophysiological processes that involve bioenergetic failure, acidosis, loss of cell homeostasis, excitotoxicity, and disruption of the blood-brain barrier. All of these mechanisms contribute to neuronal death, mainly via apoptosis or necrosis. The immune system is involved in this process in the early phases after brain injury, which contributes to potential enlargement of the infarct size and involves the penumbra area. Whereas inflammation and the immune system both exert deleterious effects, they also contribute to brain protection by stimulating a preconditioning status and to the concomitant repair of the injured parenchyma. This review describes the main phases of the inflammatory process occurring after arterial cerebral occlusion, with an emphasis on the role of single mediators.

Stroke, including acute ischaemic stroke and intracerebral haemorrhage, results in neuronal cell death and the release of factors such as damage-associated molecular patterns (DAMPs) that elicit localised inflammation in the injured brain region. Such focal brain inflammation aggravates secondary brain injury by exacerbating blood-brain barrier damage, microvascular failure, brain oedema, oxidative stress, and by directly inducing neuronal cell death. In addition to inflammation localised to the injured brain region, a growing body of evidence suggests that inflammatory responses after a stroke occur and persist throughout the entire brain. Global brain inflammation might continuously shape the evolving pathology after a stroke and affect the patients' long-term neurological outcome. Future efforts towards understanding the mechanisms governing the emergence of so-called global brain inflammation would facilitate modulation of this inflammation as a potential therapeutic strategy for stroke.