Abstract
The present in vitro study showed that IL-2/IL-2R antibody complex facilitates Treg-induced neuroprotection in the oxygen glucose deprivation/reoxygenation (OGD/R) model of stroke. First, we examined the role of IL-2/IL-2R-treated Tregs in OGD/R-exposed rat primary cortical cells (PCCs), which represent the cell type of the ischemic gray matter in the stroke brain. Here, OGD/R induced cell death, which was attenuated by Tregs and more robustly by IL-2/IL-2R-treated Tregs, but not by IL-2/IL-2R treatment alone. Second, we next assessed IL-2/IL-2R effects in OGD/R-exposed human oligodendrocyte progenitor cells (OPCs), which correspond to the white matter injury after stroke. Results revealed that a similar pattern neuroprotection as seen in the gray matter, in that OGD/R triggered cell death, which was ameliorated by Tregs and more effectively by IL-2/IL-2R-treated Tregs, but IL-2/IL-2R treatment alone was not therapeutic. Third, as we begin to understand the mechanism underlying IL-2/IL-2R engagement of Tregs, we investigated the inflammatory response in OGD/R-exposed human neural progenitor cells (NPCs), which recapitulate both ischemic gray and white matter damage in stroke. Similar to PCCs and OPCs, OGD/R produced cell death and was blocked by Tregs and more efficiently by IL-2/IL-2R-treated Tregs, whereas IL-2/IL-2R treatment alone did not alter the ischemic insult. Moreover, the inflammatory marker, TNF-α, was upregulated after OGD/R, dampened by both Tregs and more efficiently by IL-2/IL-2R-treated Tregs but more pronounced in the latter, and not affected by IL-2/IL-2R treatment alone, suggesting IL-2/IL-2R-Treg-mediated modulation of inflammatory response in stroke. Altogether, these observations support the use of IL-2/IL-2R treatment in enhancing the anti-inflammatory effects of Tregs in stroke.
Highlights
Stroke continues to be one of the most widespread causes of disability and death in adult populations and is projected to amount to more than 200 billion dollars annually in the United States by 2030 (Benjamin et al, 2019)
The role of IL-2/IL-2R in facilitating T-regulatory cells (Tregs)-induced neuroprotection was initially explored in oxygen glucose deprivation/reoxygenation (OGD/R)-exposed primary cortical cells (PCCs), which represented the cell type of the ischemic gray matter in the stroke brain (Fig. 2)
Pairwise comparisons revealed that OGD/R-exposed PCCs had a significantly improved cell survival in response to both IL-2/ IL-2R-Treg treatment and Treg treatment (p < 0.0001), while cell viability with IL-2/IL-2R treatment alone was comparable to that of the media control treatment group (p > 0.05)
Summary
Stroke continues to be one of the most widespread causes of disability and death in adult populations and is projected to amount to more than 200 billion dollars annually in the United States by 2030 (Benjamin et al, 2019). There is a significant increase in Tregs over several weeks (Hori et al, 2003) Such endogenous Treg upregulation is not sufficient to halt the progression of the secondary cell death, suggesting that further enhancement and mobilization of Tregs are needed. Treatment with IL-2/IL-2R complex reduces stroke-induced inflammation and neurological deficits, coincident with increased Tregs in vivo (Mao et al, 2017). The concept of IL-2/IL-2R complex-mediated Treg approach represents a novel stroke treatment in that it affords a wider therapeutic window, recapitulates a pharmacologic ligand–receptor interaction, and acts by regulating the inflammation-plagued secondary cell death (Zhang et al, 2018). Our overarching hypothesis was that if IL-2/IL-2R complex plays a key role in Tregs’ therapeutic effects, their combined treatment would produce more robust attenuation of OGD/R-exposed cell death compared to stand-alone treatments of IL-2/IL-2R complex or Tregs
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