The meningeal and choroidal infiltration routes for leukocytes in stroke

Abstract

Stroke is a major health burden as it is a leading cause of morbidity and mortality worldwide. Blood flow restoration, through thrombolysis or endovascular thrombectomy, is the only effective treatment but is restricted to a limited proportion of patients due to time window constraint and accessibility to technology. Over the past two decades, research has investigated the basic mechanisms that lead to neuronal death following cerebral ischemia. However, the use of neuroprotective paradigms in stroke has been marked by failure in translation from experimental research to clinical practice. In the past few years, much attention has focused on the immune response to acute cerebral ischemia as a major factor to the development of brain lesions and neurological deficits. Key inflammatory processes after stroke include the activation of resident glial cells as well as the invasion of circulating leukocytes. Recent research on anti-inflammatory strategies for stroke has focused on limiting the transendothelial migration of peripheral immune cells from the compromised vasculature into the brain parenchyma. However, recent trials testing the blockage of cerebral leukocyte infiltration in patients reported inconsistent results. This emphasizes the need to better scrutinize how immune cells are regulated at the blood–brain interface and enter the brain parenchyma, and particularly to also consider alternative cerebral infiltration routes for leukocytes, including the meninges and the choroid plexus. Understanding how immune cells migrate to the brain via these alternative pathways has the potential to develop more effective approaches for anti-inflammatory stroke therapies.

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

“…In addition, a study in C57BL/6 mice revealed that M2-like macrophages were able to infiltrate the ischaemic hemisphere via the choroid plexus-cerebrospinal fluid (CSF) route, thus suggesting that autologous transplantation of M2-like microglia into the CSF might be a promising treatment strategy for ischaemic stroke [158]. Apart from the epithelial cells of the choroid plexus, there are two other routes for leukocyte migration from the blood into the brain parenchyma, i.e., BBB and the meningeal blood circulation, each of which could be exploited by microglia [159,160].…”

Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

“…Specifically, human senescent cells up-regulate MICA, and ULBP2, ligands for the stimulatory receptor NKG2D (Antonangeli et al, 2019). Given the CNS is under immune privilege, T-cells, NKs, and peripheral macrophages normally have limited access to the meninges and choroid plexus and far-limited access to the CNS parenchyma (Galea et al, 2007;Korin et al, 2017;Benakis et al, 2018). Thus, regardless of which CNS cell types undergo senescence, the clearance of senescent cells is likely limited in healthy non-aged individuals.…”

Filling the gaps on stroke research: Focus on inflammation and immunity

“…In the past few years, research on anti-inflammatory strategies for stroke has focused on limiting the transendothelial migration of peripheral immune cells into the brain parenchyma, aiming to reduce stroke severity. These studies are based on the idea of endothelial transmigration of peripheral immune cells through the BBB, but new evidence suggests that there are other pathways at least just as important (if not more): migration through the meninges and choroid plexus (ChP), (for a complete review, see ( Benakis et al, 2018 ).…”

“…However, VCAM as well as ICAM-1 are not expressed on ChP EC ( Steffen et al, 1996 ). Hence, lymphocytes in the ChP vasculature have no access to these adhesion molecules and blocking of these will not affect the ChP infiltration route ( Benakis et al, 2018 ). In contrast, Fingolimod works by promoting lymphocyte retention in the thymus and lymph nodes ( Mandala et al, 2002 ) and thus reduces the number of circulating lymphocytes independently of adhesion molecules expression at the various migration routes, which might explain why currently the only positive results on treatment efficacy are obtained with this drug in patients with stroke ( Benakis et al, 2018 ).…”