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Stroke; Neuroinflammation; Immunomodulation; Microglia; Astrocytes; T cells; Neurovascular unit; Brain repair

Introduction

Stroke, encompassing both ischemic and hemorrhagic subtypes, results from a disruption of blood supply to the brain, leading to neuronal injury and subsequent neurological deficits. The immediate aftermath of stroke is characterized by a complex series of events, including excitotoxicity, oxidative stress, and inflammation. While the initial inflammatory response is crucial for clearing cellular debris and initiating tissue repair, its persistence or dysregulation can exacerbate neuronal damage and hinder functional recovery. The intricate communication between the nervous and immune systems, termed neuroimmune cross-talk, plays a pivotal role in shaping the post-stroke microenvironment and determining the trajectory of recovery. This review provides a synthesis of current research on this complex interplay, focusing on the dynamic interactions between immune cells, both resident and peripheral, and neuronal cells in the post-stroke brain, and their influence on recovery processes.  

Results

The neuroimmune response after stroke is a dynamic and multifaceted process involving a complex interplay of various cell types and signaling molecules. Within the CNS, microglia, the resident immune cells of the brain, are rapidly activated following stroke [1-3]. Initially, microglia adopt a pro-inflammatory (M1) phenotype, releasing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which contribute to secondary neuronal damage. However, microglia can also transition to an anti-inflammatory (M2) phenotype, promoting tissue repair and resolution of inflammation . This phenotypic switch is crucial for promoting neurogenesis, angiogenesis, and synaptic plasticity, all of which are essential for functional recovery. Astrocytes, another key glial cell type, also play a significant role in post-stroke neuroinflammation and repair. Reactive astrocytes can contribute to both neuroprotection and neurotoxicity depending on the context. They can form a glial scar, which can limit axonal regeneration but also provide structural support and limit the spread of inflammation . Peripheral immune cells, including neutrophils, monocytes, and lymphocytes, infiltrate the brain parenchyma after stroke, further contributing to the inflammatory response. Neutrophils are among the first immune cells to infiltrate the ischemic brain, releasing proteases and reactive oxygen species that can exacerbate neuronal damage [4]. Monocytes differentiate into macrophages in the brain and can contribute to both inflammation and resolution depending on their activation state. Lymphocytes, particularly T cells, also play a complex role in stroke recovery. Some T cell subsets, such as regulatory T cells (Tregs), can exert neuroprotective effects by suppressing inflammation and promoting neurotrophic factor release . However, other T cell subsets, such as Th1 and Th17 cells, can contribute to neuroinflammation and neuronal damage. The neurovascular unit (NVU), composed of neurons, glial cells, endothelial cells, and pericytes, is a critical structural and functional unit in the brain. Stroke disrupts the integrity of the NVU, leading to blood-brain barrier (BBB) breakdown and increased permeability, which facilitates the infiltration of peripheral immune cells into the brain . This BBB disruption also allows for the entry of serum proteins and inflammatory mediators into the brain parenchyma, further exacerbating neuroinflammation. The resolution of inflammation is a crucial aspect of stroke recovery. Failure to resolve inflammation can lead to chronic neuroinflammation, which can hinder long-term functional recovery. Several mechanisms are involved in the resolution of inflammation, including the production of anti-inflammatory cytokines, the clearance of cellular debris, and the activation of specialized pro-resolving lipid mediators (SPMs) [5-7]. These SPMs, such as resolvins and protectins, promote the clearance of apoptotic cells, inhibit neutrophil infiltration, and promote macrophage polarization towards an M2 phenotype, ultimately contributing to tissue repair and regeneration. Recent research has also focused on the role of the gut-brain axis in stroke recovery. The gut microbiota can influence systemic inflammation and subsequently impact neuroinflammation after stroke [8]. Dysbiosis, an imbalance in the gut microbiota, has been linked to increased inflammation and poorer stroke outcomes. Therefore, modulating the gut microbiota through interventions such as probiotics or fecal microbiota transplantation is being explored as a potential therapeutic strategy. Furthermore, genetic factors can influence the neuroimmune response after stroke and impact recovery outcomes. Polymorphisms in genes encoding inflammatory cytokines, receptors, and signaling molecules can affect the magnitude and duration of the inflammatory response . For instance, variations in genes encoding TNF-α and IL-1β have been associated with altered stroke outcomes. Finally, recent studies have explored the potential of immunotherapeutic interventions for promoting stroke recovery. These interventions include targeting specific cytokines, modulating immune cell activity, and promoting the resolution of inflammation . For example, administration of IL-10 or Tregs has shown promise in preclinical studies by reducing inflammation and improving functional outcomes.  

Discussion

The findings presented in this review highlight the complex and dynamic nature of neuroimmune cross-talk in stroke recovery. The intricate interactions between resident and peripheral immune cells, as well as the NVU, play a critical role in shaping the post-stroke microenvironment and influencing the trajectory of recovery. While the initial inflammatory response is necessary for clearing cellular debris and initiating tissue repair, its persistence or dysregulation can exacerbate neuronal damage and hinder functional recovery. The resolution of inflammation is therefore a crucial aspect of promoting long-term recovery. Understanding the precise mechanisms involved in neuroimmune cross-talk is crucial for developing targeted therapeutic interventions. Immunomodulatory therapies, such as targeting specific cytokines, modulating immune cell activity, promoting the resolution of inflammation, and targeting the gut-brain axis, hold promise for improving stroke outcomes. However, further research is needed to identify optimal therapeutic targets, timing of interventions, and personalized approaches based on individual patient characteristics.  

Conclusion

Neuroimmune cross-talk plays a crucial and dynamic role in stroke recovery. The complex interplay between resident and peripheral immune cells, as well as the NVU, shapes the post-stroke microenvironment and influences recovery processes. A better understanding of these intricate mechanisms is essential for developing effective immunotherapeutic strategies to promote neurorestoration and improve functional outcomes for stroke patients. Future research should focus on identifying specific therapeutic targets, optimizing the timing of interventions, and developing personalized approaches to maximize the benefits of immunomodulatory therapies in stroke recovery.

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