Targeting neutrophils as a novel therapeutic strategy after stroke

Abstract

Stroke is followed by an intricate immune interaction involving the engagement of multiple immune cells, including neutrophils. As one of the first responders recruited to the brain, the crucial roles of neutrophils in the ischemic brain damage are receiving increasing attention in recent years. Notably, neutrophils are not homogenous, and yet there is still a lack of full knowledge about the extent and impact of neutrophil heterogeneity. The biological understanding of the neutrophil response to both innate and pathological conditions is rapidly evolving as single-cell-RNA sequencing uncovers overall neutrophil profiling across maturation and differentiation contexts. In this review, we scrutinize the latest research that points to the multifaceted role of neutrophils in different conditions and summarize the regulatory signals that may determine neutrophil diversity. In addition, we list several potential targets or therapeutic strategies targeting neutrophils to limit brain damage following ischemic stroke.

Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

“…Our findings also demonstrate that SA administration significantly decreases the infiltration of neutrophils and macrophages into the brain after tMCAO in mice, without altering the cell number of neutrophil and macrophages in the peripheral circulation. Blood-derived neutrophils are crucial leukocytes that infiltrate into the ischemic brain (Cai et al 2020;Chen et al 2021).They are detected within 30 min, peaking between days 1-3 after ischemic (Jickling et al 2015). Neutrophils play a major pathological role in acute ischemic injury resulting in severe endothelial damage, destruction of adjacent blood vessels, and in some cases hemorrhagic transformation (Perez-de-Puig et al 2015).…”

Perioperative stroke: A perspective on challenges and opportunities for experimental treatment and diagnostic strategies

“…The idea is supported by the fact that many experimental stroke treatment strategies target neuroinflammation which seems to play a prominent pathophysiological role in PS. 31 In general, experimental treatments should be compatible to recanalization procedures, but may also be applied in PS patients being ineligible for recanalization. 15,16 However, feasibility, safety, and potential efficacy of experimental treatments must be reviewed considering the particular clinical circumstances in which they would be applied for PS.…”

Potential nanotherapeutic strategies for perioperative stroke

“…42 These pathological and biochemical changes at the cellular and molecular levels further spread to neighboring cells, activating a series of enzymatic cascade reactions that eventually lead to the cell membrane and mitochondrial damage and production of RONS 43,44 ; the production of RONS can further damage mitochondria and DNA, eventually leading to cellular necrosis or apoptosis. [45][46][47][48] Inflammatory mediators or cytokines secreted by necrotic or apoptotic cells activate resting microglia in the brain and promote the invasion and infiltration of peripheral neutrophils and macrophages 49,50 ; activated microglia in the brain can further converge and aggregate toward damaged neurons, 51 mediating the release of pro-inflammatory factors, and start a vicious circle, aggravating neuronal damage. [52][53][54][55]…”