To suffer a stroke is one the uglier and more abrupt system failures of aging. A vital blood vessel in the brain is either blocked by the biological debris of clots and fatty deposits on blood vessel walls, or more rarely the blood vessel suffers a structural failure of its walls due to forms of cellular and molecular damage that weaken, restructure, and stiffen this tissue. The higher blood pressure that accompanies age, for a collection of reasons that are only mostly avoidable, raises the odds of disaster. Thus a part of the brain is either deprived of oxygen or flooded with blood, and in either case cells die and a fragment of the brain - and the mind it hosts - is lost or greatly impaired, often permanently.
The ultimate objective of rejuvenation biotechnology after the SENS model of is to remove the root causes that lead to stroke, as for all age-related conditions. Break down the metabolic waste that stiffens blood vessels and indirectly raises blood pressure; restore stem cell populations to more aggressive repair of failing tissues; and more besides. Among the "more besides," is it the case that stroke has immune dysfunction among its noteworthy contributing causes? The immune system fails in characteristic ways with aging, among them a growth in chronic inflammation: even as the immune system becomes unable to adequately police the body in search of pathogens and rogue cells, it is constantly overactive, in a state of inflammation. This progression towards dysfunction is termed inflammaging, but there may be comparatively straightforward ways to turn it back at least some of the way. This might be achieved by crudely rebalancing the internal configuration of the immune system, destroying one class of cells that serve little useful purpose, but have grown too numerous. Their numbers block the generation of effective new immune cells, but if winnowed that would change.
Open access papers in the latest issue of Aging and Disease argue for the immune dysfunction contribution to stroke, mediated by inflammation:
Stroke is a leading cause of long-term disability and the second leading cause of death globally. Approximately 795,000 strokes are reported each year in the US, 87 percent of which are ischemic. The direct medical cost associated with stroke in 2009 was approximately $22.8 billion, with an additional $13.8 billion in indirect costs associated with lost productivity, unemployment, rehabilitation, and follow-up care.
It is interesting to consider whether a common mechanism of immune dysfunction underlies many complex diseases, such as stroke, heart disease, myocardial infarction, and atherosclerosis. While it is possible that the immune system is similarly altered, gene-environment interactions may control the timing or severity of the dysfunction, and epigenetic modifications may provide a common molecular mechanism to link the immune response among different disease states. Our knowledge of the epigenetic control of the immunological consequences of ischemic stroke is limited and requires a new approach to clinical and pre-clinical studies.
It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response.
Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke.
The complex, multifaceted cascade of events that results from brain deprivation of oxygen, glucose, and other essential nutrients to the brain causes dysfunction. During ischemia, glutamate stored within brain cells is released when cells are hyperactive or die. Furthermore, brain and immune cells produce reactive oxygen species (ROS), and restoration of blood flow in the occluded vessel generates additional ROS. ROS activate endothelial cells and cause oxidative stress. Oxidative stress and the induction of the inflammatory cascade leads to the breakdown of the blood-brain barrier allowing activated blood-borne immune cells such as neutrophils and T-cells to infiltrate and accumulate in the ischemic brain tissue. Along with the accumulation of activated immune cells, microglia in the brain become activated after cerebral ischemia. Activated microglia secrete pro-inflammatory mediators such as cytokines.
As cells die and brain tissue is damaged, molecular danger signals further potentiate the inflammatory response by activating more microglia and infiltrating leukocytes in a feed-forward response producing more deleterious pro-inflammatory cytokines. These inflammatory changes after ischemia lead to an increase in neuronal cell death resulting in a larger infract volume and worse neurological outcome. Inflammation is a key player in brain damage during cerebral ischemia; however, inflammation aiding in repair and recovery after cerebral ischemia can be beneficial.
It is clear that cytokines play an important role in the pathophysiology of stroke, and the loss in balance between pro-inflammatory and anti-inflammatory cytokines after stroke affects infarct size and functional outcome. Thus, focusing on one cytokine only as a potential biomarker or a therapeutic target likely will not be advantageous in stroke. Future work needs to elucidate the temporal profile of cytokines in the periphery in human and experimental stroke studies to determine which cells contribute to the elevation of cytokines in the brain and blood and to understand how they work in concert to provide neuroprotection or increase neurotoxicity.
The crosstalk between the immune system and the brain is still not well understood. Using cytokines as biomarkers or therapeutic targets may be beneficial to understand the post-ischemic immune response and its effects on outcome clinically and to modulate the post-ischemic immune response to limit tissue damage. However, modulation of the immune response can also be detrimental after stroke; thus, it is imperative that further clinical and experimental studies be pursued to better understand the complex interaction between the immune system and the brain after stroke.