Neuroinflammation: friend and foe for ischemic stroke

Abstract

Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.

Keywords: Blood-brain barrier; Ischemia; Neuroinflammation; Stroke.

Fig. 1

Schematic representation of the detrimental events following ischemic stroke. Stroke potentiates a cascade of ischemic events that leads to impairment of NVU resulting in BBB damage. Neurovascular unit is made of highly specialized and polarized endothelial cells interconnected by tight junction proteins that seal the brain capillaries. Astrocytes, microglia, and pericytes provide structural and functional support to the BBB. Ischemic stroke leads to NVU remodeling due to detachment of astrocytic endfoot, pericyte detachment, vasconstriction, dysfunction of neurovascular coupling, activation of microglia, and blood vessel rupture

Fig. 2

Schematic representation of post-ischemic inflammatory response in stroke. Initial ischemic event leads to oxidative stress and excitotoxicity which causes activation of microglia and astrocyte resulting in secretion of cytokines, MMP, and GFAP. These proinflammatory factors leads to upregulation of cell adhesion molecules such as ICAM-1 and selectins on endothelial cells causing inflow of blood derived inflammatory cells such as neutrophils, macrophages, and lymphocytes to the ischemic area. In addition, danger-associated molecular patterns (DAMPs) are released by dying neurons that in turn activates microglia and peripheral immune cells (neutrophil, macrophage, and lymphocyte) resulting in production of proinflammatory factors causing further activation of microglia and astrocyte. These pathological events lead to neuronal death and further increase damage to the ischemic brain

Fig. 3

Apoptotic mechanisms involved in ischemic cell death

Fig. 4

Neuropathological mechanisms in ischemic stroke and respective targets assessed in clinical trials with and without beneficial effects