The Local and Peripheral Immune Responses to Stroke: Implications for Therapeutic Development

Abstract

The immune response to stroke is an exciting target for future stroke therapies. Stroke is a leading cause of morbidity and mortality worldwide, and clot removal (mechanical or pharmacological) to achieve tissue reperfusion is the only therapy currently approved for patient use. Due to a short therapeutic window and incomplete effectiveness, however, many patients are left with infarcted tissue that stimulates inflammation. Although this is critical to promote repair, it can also damage surrounding healthy brain tissue. In addition, acute immunodepression and subsequent infections are common and are associated with worse patient outcomes. Thus, the acute immune response is a major focus of researchers attempting to identify ways to amplify its benefits and suppress its negative effects to improve short-term recovery of patients. Here we review what is known about this powerful process. This includes the role of brain resident cells such as microglia, peripherally activated cells such as macrophages and neutrophils, and activated endothelium. The role of systemic immune activation and subsequent immunodepression in the days after stroke is also discussed, as is the chronic immune responses and its effects on cognitive function. The biphasic role of inflammation, as well as complex timelines of cell production, differentiation, and trafficking, suggests that the relationship between the acute and chronic phases of stroke recovery is complex. Gaining a more complete understanding of this intricate process by which inflammation is initiated, propagated, and terminated may potentially lead to therapeutics that can treat a larger population of stroke patients than what is currently available. The immune response plays a critical role in patient recovery in both the acute and chronic phases after stroke. In patients, the immune response can be beneficial by promoting repair and recovery, and also detrimental by propagating a pro-inflammatory microenvironment. Thus, it is critical to understand the mechanisms of immune activation following stroke in order to successfully design therapeutics.

Neuroinflammation and microglia/macrophage phenotype modulate the molecular background of post-stroke depression: A literature review

“…With a close shift, monocyte-derived macrophages pass through the injured blood-brain barrier, penetrate the core lesion and also deploy at the perilesional zone, the penumbra. Peripheral monocytes are recruited through monocyte chemoattractant protein (MCP-1 or CCL-2), and due to danger signals received from the environment, switch to a pro-inflammatory phenotype, releasing various metalloproteinases and reactive oxygen species (48). In the chronic recovery phase, in an IL-4, IL-10, and transforming growth factor β (TGFβ) containing milieu, infiltrating macrophages may switch their differentiation path to an anti-inflammatory phenotype.…”

“…After the onset of stroke, injured neurons and glial cells quickly activate the neighboring astrocytes through the expression of damage-associated molecular patterns (high mobility group box-1, HMGB1; peroxiredoxins, PRX; galectin-3) ( 47 ). These cells, along with resident microglia, secrete a set of pro-inflammatory cytokines (IL-1β, IL-6, IFNγ, TNFα), chemokines, and matrix metalloproteinases, like MMP-9, contributing to the disruption of the blood-brain barrier ( 48 ). Neuronal-derived fractalkine (CX3CL1) further amplifies microglia activation.…”

“…Th17 cells are also over-represented and activated ( 52 ). Recent studies underscore the central role of CD4 + /CD25 + /Foxp3 + or CD4 + /CD25 + /CD127 - regulatory T cells, which proliferate and are detectable in ischemic lesions up to 30 days ( 48 , 53 ). A high number of Tregs at 48 h is associated with the right functional outcome; reversely, a decreased number indicates a higher probability for early neurological deterioration ( 53 , 54 ).…”

“…IL-10 producer Tregs are susceptible to antagonize IFNγ and TNFα ( 55 ). B lymphocytes are also detectable in the invader cell populations; as B-cell deficient mice show larger infarct volumes and more severe neurological deficit, their role seems to be somewhat protective, especially in the presence of IL-10( 48 ). However, it was also documented that B-cells and autoantibodies probably induce delayed cognitive deficit and dementia ( 56 ).…”

Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway

“…Cerebral ischemic stroke remains the leading cause of the death and disability worldwide, despite progress in reperfusion therapies. Considerable empirical evidence has demonstrated that inflammatory response of microglia/macrophages to cerebral ischemia acts a vital part in varied phases of stroke pathobiology and outcome [1]. Excessive activation of proinflammatory cytokines, neural cell death, the blood-brain barrier, and neurogenesis disruption jointly lead to postischemic brain injury [2].…”