The impact of cytokines in neuroinflammation-mediated stroke

Cerebral stroke is ranked as the third most common contributor to global mortality and disability. The involvement of inflammatory mechanisms, both peripherally and within the CNS, holds significance in the pathophysiological cascades following the initiation of stroke. After the onset of acute stroke, predominantly ischemic, a subsequent phase of neuroinflammation ensues. It is a dual-effect process that not only exacerbates injury, leading to cell death, but paradoxically, it also serves a shielding role in facilitating recovery. Cytokines serve as pivotal mediators within the inflammatory cascade, actively contributing to the progression of ischemic damage. Stroke is followed by increased expression of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, etc. leading to the recruitment and stimulation of glial cells and peripheral leukocytes at the site of injury, promoting neuroinflammation. Cytokines can directly induce neuronal injury and death through various mechanisms, including excitotoxicity, oxidative stress, HPA-axis activation, secretion of matrix metalloproteinase and apoptosis. They can also amplify the inflammatory response, leading to further neuronal damage. Therapeutic strategies aimed at modulating cytokine release, immune response and cytokine signalling or activity are being explored as potential interventions to mitigate neuroinflammation and its detrimental effects in stroke. In this review, we have given a concise summary of our current knowledge of the function of various cytokines, brain inflammation and various signalling and molecular pathways including JAK/STAT3, TGF-β/Smad, MAPK, HMGB1/TLR and NF-κB modulated cytokines regulation in stroke. Therapeutic agents such as MCC950, genistein, edaravone, minocycline, etc. targeting various cytokines-associated signalling pathways have shown efficacy in preclinical and clinical trials reducing the pathophysiology of the illness were also addressed in this study.