Neuroinflammation in Stroke
At a glance
Introduction of Neuroinflammation in Stroke
Neuroinflammation is the brain's immune response to stimuli like cerebral ischemia, involving immune cells, blood vessels, and various molecular changes. It's crucial in stroke pathophysiology, starting within minutes of an ischemic event and lasting days. In hemorrhagic stroke, it's initiated by blood byproducts in the subarachnoid space or brain tissue.
In stroke, the inflammation is activated by a set of resident and infiltrating peripheral immune cells (microglia, astrocytes, endothelial cells, leukocytes) that secrete proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). These inflammatory mechanisms are capable of worsening brain injury with secondary damage, tissue repair and recovery delays, and post-stroke complications. Yet neuroinflammation can be an efficient effect too, by cleaning out cells and healing tissues. The dual roles of neuroinflammation in stroke are complex, necessitating further research to create targeted therapies. Understanding these mechanisms is essential for minimizing secondary damage and improving stroke outcomes.
Fig.1. Schematic representation of post-ischemic inflammatory response in stroke. (Jayaraj, et al., 2019)
At Ace Therapeutics, we specialize in analyzing the neuroinflammatory mechanisms of stroke. Our services cover a wide range of approaches, including molecular analysis, cellular studies, and advanced imaging techniques. We can analyze the neuroinflammatory process and BBB destruction in stroke involving multiple signaling pathways.
Related Services
Impact of Microglia on Stroke
Microglia are innate immune cells built into the brain, making up about 5-20% of the neuroglia. They transform in morphological and phenotypic ways after brain ischemia, shifting and morphologically adapting to local inputs. Microglia around the injured tissue migrate towards the ischemic site and stay associated with neurons for "capping", to recognize and rapidly phagocytose dead neurons early after death.
In the brain after an ischemic event, activated microglia function much like macrophages: they phagocytose and release cytokines and MMPs that can compromise the BBB and exacerbate post-ischemic damage. Based on these signals, stimulated microglia release cytotoxic molecules such as reactive oxygen species, NO, glutamate and histamine, pro-inflammatory mediators (IL-1, TNF-α, IL-6, IFN-γ) along with neurotrophic and anti-inflammatory mediators (IL-4, IL-10, brain-derived neurotrophic factor (BDNF), neurotrophin-3, -4 and -5.
Impact of Astrocytes on Stroke
Astrocytes and microglia are the major immunocompetent cells of the CNS. They are actively involved in the control of ionic and aqueous homeostasis, release of neurotrophic factors, clearance of transmitters released during synaptic activity, shuttling of metabolites and waste products, and in the formation of the BBB. Astrocytes can control the immune system by inhibiting T cell and monocyte activation. Some reactive astrocytes after ischemic stroke can also become unspecialized phagocytes to clear the infarct.
Astrocytes keep glutamate in check under average circumstances by converting glutamate to glutamine for neuronal recycling. But in the case of brain injury, they lose glutamate uptake and become excitotoxic.
In the wake of cerebral ischemia, reactive gliosis sets in with activation of astrocytes and the production of glial fibrillary the acidic protein (GFAP). Activated astrocytes also release inflammatory mediators – cytokines and inducible nitric oxide synthase (iNOS) – which are also part of the whole-brain healing process. Astrocytes in general, then, are involved in the healing process as well as post-ischemic injury.
Impact of Leukocytes on Stroke
Leukocytes play a key role in neuroinflammation and subsequent neurovascular injury following cerebral ischemia, and leukocytosis is a signature of that. These neutrophils are the first leukocytes to make a return after injury, triggering inflammation and collateral damage by releasing pro-inflammatory molecules like nitric oxide synthase and MMPs. Active leukocytes can also release reactive oxygen species (ROS) and other blood vessel-clearing proteases. They stick to the endothelium and can clog the microvascular system, causing damage to the integrity of blood vessels.
Aside from neutrophils, monocytes and lymphocytes invade the ischemic brain as well. Both intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, and integrin interactions on leukocytes, cause their aggregation on vessel walls. Furthermore, the expression of platelet and endothelial cell adhesion molecule-1 (PECAM-1) and junctional proteins helps neutrophil diapedesis in the BBB. Learn more about leukocyte function in ischemic stroke for treatment options that minimize brain damage and facilitate recovery.
Pericytes in Stroke Inflammatory Response
Pericytes are smooth muscle cells that encase macrophages, are paired with basal lamina, and are involved in angiogenesis and injury. Moreover, pericytes regulate neurovascular unit physiology through microvascular stability, tight junction proteins, and microvessel diameter. In acute ischemic stroke, pericytes act in two roles in the inflammatory cascade. They have pro-inflammatory and immune-regulatory effects and they also help to defend the brain from leukocytes. Pericytes are phagocytic and migratory following ischemic injury, and can develop into cell types that are phagocytic, such as microglia cells. Pericyte depletion increases leukocyte invasion. Brain microvascular pericytes also release toll-like receptor 4 (TLR4) and are pro-inflammatory.
T Lymphocytes in Ischemic Stroke
Lymphocytes (in particular T-cells) are critical for regulating immune function during neuroinflammation following stroke. T-cells access the ischemic zone by tethering to the endothelium with adhesion molecules. Infiltrated CD4 and CD8 T-cells release IL-17 soon after stroke, worsening ischemic damage. On the other hand, regulatory T-cells (T-regs) are needed for over-excitability and immune tolerance. T-regs can be activated and recruited to the injury site, where they influence the immune system and repair tissues via the release of anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-β ). They also boost neuroprotective substances like BDNF and vascular endothelial growth factor (VEGF) that aid in angiogenesis and neuronal survival.
Cytokine Involvement in Stroke
Cytokines are immunomodulators that are central to cell activation, proliferation and differentiation. When inflammation, BBB degeneration, and BBB dysfunction are present in ischemic stroke, pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α are generated quickly during the injury and can exacerbate the condition. Cytokines, on the other hand, like IL-10 and TGF-β, are neuroprotective, reducing inflammation and repairing tissues. All in all, cytokines are multifaceted in their pathogenesis of ischemic stroke and their inhibition could be used to treat stroke.
Chemokine Involvement in Stroke
Chemokines also promote the release of leukocytes and modulate their distribution in lymph nodes and tissues (astrocyte and microglia are the main sources in the brain). Different chemokine genes (CXCL1, 2, 5, IL-8, CCL20) get activated by inflammation. But if microglia are overactivated, that can lead to a prolonged inflammatory response, further damaging the brain. Chemokines could be an area for therapy of stroke.
Transcription Factors in Stroke
Neuroinflammation is tightly controlled by transcription factors. We already know that ischemic neuronal injury and/or ischemic tolerance are prevented by cAMP response element binding protein (CREB), peroxisome peroxisome proliferator-activated receptor (PPAR)α, PPARγ, and p53 proteins being activated. But induction of interferon regulatory factor-1 (IRF-1) and transcription factor-2, signal transducer and activator of transcription 3 (STAT3), NF-κB, early growth response-1 (Egr1) and C/EBPβ drives neuroinflammation and neuronal death after cerebral ischemia.
In summary, by learning what those transcription factors do in the post-ischemic brain, new diagnostic and therapeutic interventions for ischemic stroke could emerge. Transcription factors are key regulators of pro-inflammatory gene transcription in the post-ischemic brain and cause microglia to activate and polarise. Future research into these pathways could shed light on new ideas and directions for diagnosing and treating ischemic stroke.
- Jayaraj, R. L., et al. (2019). Neuroinflammation: friend and foe for ischemic stroke. Journal of neuroinflammation, 16, 1-24.
