Minnerup, J. | Search bioRxiv

bioRxiv2022

The nuclear receptor NR4A1 restrains neutrophil granulocyte mediated brain damage in cerebral ischemia

Immigration and activation of immune cells play a significant role in damage progression after ischemic stroke. It has been shown that the nuclear receptor NR4A1 exerts a crucial role within the inflammatory response of various immune diseases via regulating immune cell activation. In this study, we investigated the role of NR4A1 on the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage limiting effect after ischemic stroke through immigrating neutrophil granulocytes. Importantly, NR4A1-activation with its ligand Cytosporone-B improves functional outcome and diminishes brain damage. Therefore, modulation of NR4A1 is a promising therapeutic target in the treatment of stroke.

neuroscience↗

bioRxiv2021

A preclinical randomized multicenter trial of anti-IL-17A treatment for acute ischemic stroke

Multiple consensus statements have called for preclinical randomized controlled trials (pRCT) to improve translation in stroke research. Here, we investigated the efficacy of IL-17A neutralizing antibodies in a multicentric pRCT using a murine stroke model. C57/Bl.6 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Mice were randomly allocated (1:1). Either anti-IL-17A (500 {micro}g) or isotype antibody (500 {micro}g) were administered 1 h after tMCAO. Primary analysis of infarct volumes was done by MRI after three days. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the analysis. Mixed model analysis revealed that the IL-17A neutralization significantly reduced infarct sizes (anti IL-17A: 61.77 {+/-} 31.04 mm3; IgG control: 75.66 {+/-} 34.79 mm3; p=0.01). Secondary outcome measures showed a decrease in mortality (Hazard Ratio=3.43, 95% CI = 1.157 - 10.18; p=0.04) and neutrophil invasion into ischemic cortices. There was no difference in the neurological score. The analysis of the gut microbiome showed significant differences between centers. Taken together, this is the first positive pRCT in an ischemia reperfusion model. It suggests IL-17A neutralization as a potential target in stroke.

neuroscience↗