Neuroinflammation and fibrosis in stroke: The good, the bad and the ugly

Abstract

Stroke is the leading cause of death and the main cause of disability in surviving patients. The detrimental interaction between immune cells, glial cells, and matrix components in stroke pathology results in persistent inflammation that progresses to fibrosis. A substantial effort is being directed toward understanding the exact neuroinflammatory events that take place as a result of stroke. The initiation of a potent cytokine response, along with immune cell activation and infiltration in the ischemic core, has massive acute deleterious effects, generally exacerbated by comorbid inflammatory conditions. There is secondary neuroinflammation that promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. This highlights the need for a better understanding of the neuroinflammatory and fibrotic processes, as well as the need to identify new mechanisms and potential modulators. In this review, we summarize several aspects of stroke-induced inflammation, fibrosis, and include a discussion of cytokine inhibitors/inducers, immune cells, and fibro-inflammation signaling inhibitors in order to identify new pharmacological means of intervention.

Keywords: Cytokines; Fibrosis; Immune cell infiltration; Neuroinflammation; Perlecan; Stroke.

Fig.1.

Schematic of stroke-induced neuroinflammation. Stroke induces activation of stress signals, hypoxia, OGD, oxido-nitrosative stress, DAMPS such as high-mobility group box 1 protein (HMGB-1) derived from dying neurons, and it further activates innate microglia and other immune cells, via mediating toll like receptors (TLR), which in turn produce many pro-inflammatory cytokines, and matrix metalloproteinases (MMPs), which leads to activation of NLRP3 signaling and infiltration of immune cells and potent cytokine response and neuroinflammation. Following stroke, activated parenchymal microglial cells transforms to M1 and M2 macrophage polarization. M1 macrophages release proinflammatory cytokines whereas M2 macrophages release anti-inflammatory cytokines and inhibit neuroinflammation.