Brain-infiltrating ILC2s boost poststroke angiogenic initiation through α-CGRP production

Group 2 innate lymphoid cells (ILC2s) regulate immunity and tissue repair but are rarely found in the brain. Whether ILC2s can infiltrate the brain from bloodstream and the underlying mechanisms involved remain unclear. While ILC2s have recently been identified as key immunosuppressive players in neuroinflammation, their role in brain tissue repair remains promising but underexplored. Here, using in vivo and in vitro expansion of ILC2s, we demonstrate that ILC2s can enter the brain parenchyma from the blood circulation early after ischemic stroke in a CXCR1-dependent manner. Once in the brain, ILC2s improve long-term recovery of sensory-motor functions by promoting initiation of angiogenesis, namely angiogenic sprouting. Mechanistically, ILC2s produce α-calcitonin gene-related peptide (α-CGRP) to enhance angiogenic sprouting. ILC2s depleted of α-CGRP infiltrate the brain but fail to initiate angiogenesis. Impaired function of CGRP receptors on cerebrovascular endothelial cells abolishes the angiogenic effect of ILC2s. These findings highlight ILC2s as a promising target for promoting therapeutic angiogenesis in stroke recovery.