Stroke's Impact: Weakened Immune System And Recovery Challenges

A stroke is a life-threatening medical condition that occurs when blood flow to the brain is blocked or a blood vessel in the brain bursts. It is one of the leading causes of death and disability worldwide. The long-standing belief that stroke is exclusively a vascular disease has been challenged by extensive clinical findings of immune factors, mostly associated with inflammation.

The immune system's response to stroke is complex and not yet fully understood. The immune system's response to stroke can be both beneficial and detrimental. The innate immune system, which provides the first line of defence, is activated by the release of inflammatory molecules from injured and dead cells. This leads to neuroinflammation and further brain damage. The adaptive immune system, on the other hand, may have a protective effect by producing anti-inflammatory cytokines.

Following a stroke, the immune system can also undergo immunosuppression, making stroke patients more susceptible to infections such as pneumonia and urinary tract infections. This immunosuppression is mediated by the autonomic nervous system, particularly the sympathetic nervous system, which releases catecholamines that suppress the immune response.

The complex interplay between the immune system and stroke has important clinical implications. A better understanding of these interactions can aid in the development of new diagnostic tools and therapeutic approaches to improve patient outcomes.

The immune system's response to stroke

The innate immune system, which includes microglia, macrophages, neutrophils, and dendritic cells, plays a crucial role in the early stages of stroke. Microglia, the resident myeloid cells in the central nervous system (CNS), are the first responders to stroke. They help clear debris and repair injured tissue but can also promote inflammation and neurovascular breakdown. Neutrophils, another type of innate immune cell, are among the first to infiltrate the stroke-affected tissues and can contribute to infarct size and neurological outcomes. The role of macrophages and dendritic cells in stroke is more controversial, with some studies suggesting they have neuroprotective effects while others indicating they can be neurodegenerative.

The adaptive immune system, including T lymphocytes and B cells, becomes involved in the days following stroke. T lymphocytes, particularly cytotoxic CD8+ lymphocytes, have been implicated in acute ischemic stroke pathology and can contribute to secondary tissue injury. B cells, on the other hand, have been found to have a protective effect, possibly due to the production of anti-inflammatory cytokines.

The immune response to stroke is not limited to the brain but also has systemic effects. Stroke can lead to immunosuppression, making individuals more susceptible to infections, especially pneumonia and urinary tract infections. This immunosuppression is mediated by the autonomic nervous system, particularly the sympathetic nervous system, which suppresses the immune response and increases susceptibility to infection. Additionally, stroke can lead to alterations in the gut microbiota, which can further impact the immune system and increase the risk of infection.

Overall, the immune system's response to stroke is a complex and multifaceted process that is not yet fully understood. Further research is needed to elucidate the specific mechanisms involved and develop effective immunomodulatory therapies to improve outcomes for stroke patients.

The role of the autonomic nervous system in stroke-induced immunosuppression

The autonomic nervous system (ANS) plays a key role in the communication between the nervous and immune systems. The ANS is composed of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). After a stroke, the SNS is overactivated and releases large amounts of norepinephrine into the blood. This can have a variety of biological functions, including regulating neurons, microglia and astrokeratinocytes, as well as increasing blood pressure and heart rate. The SNS also regulates the immune system and inflammatory response to protect the body from foreign pathogens and endogenous inflammatory damage factors.

The SNS can also suppress the immune system and inflammatory response, which can be beneficial in the early stages of stroke recovery by counteracting excessive inflammatory responses to brain damage. However, prolonged immunosuppression increases the risk of infection in patients. The SNS releases norepinephrine, which activates β2-AR and limits T cell autoimmunity in the CNS through a mechanism mediated by suppression of IL-2, IFN-γ and granulocyte-macrophage colony-stimulating factor production via inducible cAMP early repressor.

The PNS, on the other hand, can antagonise various pathological mechanisms. Vagus nerve stimulation (VNS) can improve various brain diseases. VNS increases norepinephrine and acetylcholine, which inhibits inflammation through inhibition of the NF-κB pathway mediated by neuronal acetylcholine receptor subunit alpha-7 (nAChRα7). nAChRα7 is an important target for inhibiting the release of proinflammatory cytokines by macrophages and dendritic cells and is expressed in peripheral and CNS macrophages (such as microglia).

The SNS and PNS, along with the HPA axis, are important pathways for the CNS to communicate with the periphery.

The role of the hypothalamic-pituitary-adrenal axis in stroke-induced immunosuppression

The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the body's response to stress. It is comprised of the hypothalamus, the pituitary gland, and the adrenal glands. During a stressful event, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH then triggers the adrenal glands to release glucocorticoids, such as cortisol, which help the body cope with stress.

Stroke is a stressful event that can activate the HPA axis. The activation of the HPA axis during stroke has been associated with immunosuppression, which increases the risk of infections such as pneumonia and urinary tract infections. This immunosuppression is characterised by lymphopenia, upregulation of anti-inflammatory cytokines, and splenic atrophy.

The HPA axis plays a crucial role in stroke-induced immunosuppression by mediating the release of glucocorticoids. Glucocorticoids can modulate the immune response by affecting the differentiation and function of various immune cells, including B cells, T cells, and monocytes. Increased glucocorticoid levels can lead to lymphocyte apoptosis and lymphopenia, resulting in a decrease in circulating immune cells. Additionally, glucocorticoids can promote anti-inflammatory responses and suppress pro-inflammatory cytokine production, further contributing to immunosuppression.

The activation of the HPA axis during stroke has been observed in both human and animal studies. In mice infected with Angiostrongylus cantonensis, a parasite that causes central nervous system injury, the HPA axis was activated, leading to increased glucocorticoid levels and immunosuppression. Similarly, in patients with ischemic stroke, the HPA axis was activated, resulting in increased cortisol levels and immunosuppression.

The role of the HPA axis in stroke-induced immunosuppression is complex and involves interactions with other systems, such as the sympathetic nervous system and the cholinergic anti-inflammatory pathway. Furthermore, the HPA axis may also be influenced by stress mediators and inflammatory cytokines released during stroke.

Further research is needed to fully understand the mechanisms underlying the role of the HPA axis in stroke-induced immunosuppression and to develop potential therapeutic interventions to improve outcomes for stroke patients.

The role of the parasympathetic nervous system in stroke-induced immunosuppression

The parasympathetic nervous system (PNS) has been shown to have multiple therapeutic benefits in brain diseases. Its activation can suppress both brain parenchymal inflammation and peripheral inflammation, leading to neuroprotection in ischemic stroke.

The PNS can be activated by various methods, including vagus nerve stimulation (VNS), sphenopalatine ganglion (SPG) stimulation, cholinesterase inhibitors, and α7 nicotinic acetylcholine receptor (nAChRα7) agonists. The neuroprotective mechanisms of PNS activation include:

• Afferent vagus nerve pathway: The afferent vagus nerve projects to the nucleus tractus solitarius (NTS) in the medulla oblongata, which in turn projects to various brain structures, including the locus coeruleus (LC). The LC provides noradrenergic innervation to the thalamus, hippocampus, cerebral cortex, and the forebrain cholinergic system.
• Central cholinergic and efferent vagal pathway: The central cholinergic system, which includes projections from the nucleus basalis of Meynert, the medial septal nuclei, and the pedunculopontine tegmental nucleus, provides cholinergic innervation to the caudate nucleus, globus pallidus, thalamus, hippocampus, and cerebral cortex. The central cholinergic system drives the efferent vagal output.
• Parasympathetic cerebrovascular innervation: The sphenopalatine ganglion (SPG), a parasympathetic ganglion found in the pterygopalatine fossa, receives preganglionic neurons from the superior salivatory nucleus (SSN). Postganglionic neurons from the SPG provide nitroxidergic-cholinergic innervation to the major cerebral blood vessels.

The role of the PNS in stroke-induced immunosuppression involves the activation of the cholinergic anti-inflammatory pathway. This pathway is driven by the central cholinergic system in the brain, with peripheral output through the efferent vagus nerve. The effector receptor, nAChRα7, is expressed on peripheral blood macrophages as well as residential macrophages such as microglia in the brain. Activation of nAChRα7 on microglia has been shown to attenuate inflammatory responses in the brain.

Additionally, VNS has been found to cause an early release of norepinephrine from the LC, which projects to various parts of the brain, including the cerebral cortex. Norepinephrine has been shown to have anti-inflammatory effects via α1-adrenergic receptors and can stimulate the release of serotonin (5-HT) from the dorsal raphe nucleus. 5-HT has been shown to antagonize excitotoxicity by inhibiting glutamate release and downregulating the NR2B subunit of the N-methyl-aspartate receptor, which is associated with excitotoxicity.

In summary, activation of the PNS exerts a broad range of neuroprotective mechanisms in ischemic stroke, including the suppression of inflammation and excitotoxicity. Further research is needed to translate these findings into clinical practice and develop PNS activation as a therapeutic modality for acute ischemic stroke.

The impact of stroke on the lungs

Stroke can have a significant impact on the lungs, and this impact can vary depending on the type of stroke and its severity. Here are some key points regarding the impact of stroke on the lungs:

• Ischemic stroke: Ischemic stroke, the most common type of stroke, can lead to lung injury and inflammation. This is due to the interruption of blood flow to the brain, which can cause brain inflammation and subsequent systemic inflammation, including in the lungs.
• Lung inflammation: Stroke-induced lung inflammation is characterised by an increase in pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, TNF-α, and MCP-1, in the lungs. This can lead to an influx of inflammatory cells, particularly macrophages and neutrophils, into the lungs.
• Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS): While stroke can cause lung inflammation, the development of ALI or ARDS is less consistent and may depend on the severity of the stroke. Some studies have reported ALI/ARDS in a subset of stroke patients, while others have found no evidence of lung injury or oedema.
• Pulmonary complications: Stroke is associated with an increased risk of pulmonary complications such as pneumonia, ALI, and neurogenic pulmonary oedema. These complications can occur in the first few days to weeks following a stroke and are a major contributor to morbidity and mortality.
• Mechanisms: The exact mechanisms underlying the impact of stroke on the lungs are not fully elucidated. However, it is thought that brain-lung crosstalk and systemic inflammation play a role. Stroke can activate the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of catecholamines and glucocorticoids, which can have immunosuppressive effects and impact lung function.
• Clinical implications: The clinical implications of stroke-induced lung damage are significant. Pulmonary complications can worsen the prognosis of stroke patients and increase the risk of mortality and disability. Additionally, the lungs of patients who die from stroke may be suitable for transplantation if ALI/ARDS does not occur.

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