Meningeal IL-17 producing T cells mediate cognitive impairment in salt-sensitive hypertension

Santisteban, M. M.; Faraco, G.; Brea Lopez, D.; Wang, G.; Sobanko, M. J.; Sciortino, R.; Racchumi, G.; Waisman, A.; Anrather, J.; Iadecola, C.

doi:10.1101/2022.09.05.506398

bioRxiv · 10.1101/2022.09.05.506398

Meningeal IL-17 producing T cells mediate cognitive impairment in salt-sensitive hypertension

Santisteban, M. M.·Faraco, G.·Brea Lopez, D.·Wang, G.·Sobanko, M. J.·Sciortino, R.·Racchumi, G.·Waisman, A.·Anrather, J.·Iadecola, C.

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Abstract

Hypertension, a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In a mouse model of hypertension, we found that the neurovascular and cognitive dysfunction depends on IL-17, a cytokine elevated in hypertensive individuals. However, neither circulating IL-17 or brain angiotensin signaling could account in full for the dysfunction. Rather, IL-17 produced by T-cells in the dura mater was the major culprit by reaching the cerebrospinal fluid and activating IL-17 receptors on brain associated macrophages. Accordingly, depleting brain macrophages, deleting IL17-RA in brain macrophages, or suppressing meningeal T cells completely rescued cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. The data unveil a critical role of meningeal T-cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction of hypertension and suggest novel therapies to counteract the devastating effects of hypertension on cognitive health.

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Santisteban, M. M., Faraco, G., Brea Lopez, D., Wang, G., Sobanko, M. J., Sciortino, R., Racchumi, G., Waisman, A., Anrather, J., Iadecola, C.. 2022-09-06. Meningeal IL-17 producing T cells mediate cognitive impairment in salt-sensitive hypertension. https://doi.org/10.1101/2022.09.05.506398

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