The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown

Abstract

Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke.

Keywords: angiogenesis; immune cells; inflammation; ischemic stroke; neurogenesis.

Figure 1

Angiogenesis and neuronal remodeling after stroke. After stroke onset, the hypoxic and ischemic environment triggers vascular sprouting. Vascular endothelial growth factor receptor 2 (VEGFR-2) is expressed on endothelial cells (ECs; shown in gray), where it binds to VEGF-A, which initiates proliferation and protrusion of filopodia. Concomitantly, ECs secrete matrix metalloproteinases and endothelial growth factors to facilitate the migration of endothelial progenitor cells and basement membrane degradation. Microvessels are thought to support neural stem cell proliferation by supplying oxygen, nutrients, and a series of growth factors, including basic fibroblast growth factor, epidermal growth factor, and brain-derived neurotrophic factor. Newly formed blood vessels provide guidance for migration and axonal outgrowth through Laminin/β1 integrin signals.

Figure 2

Potential interaction between neutrophil and endothelium after stroke. Neutrophil may exhibit either detrimental (marked in red box) and beneficial (blue box) effects towards the endothelium after stroke. Triggered by phagocytosis, neutrophils release granular contents and formed NETs mediated by the expression of Ly6G and PAD4. In addition, the release of ROS would damage surrounding endothelium and promote the formation of NETs as well. On the contrary, the secretion of Cathepsin would induce the recruitment of circulating endothelial progenitor cell (EPC) in an N-formyl peptide receptor 2 (FPR2)-dependent manner, which promote the angiogenesis in the latter stage of stroke.

Figure 3

Subtype conversion and function of M2 macrophages. (A) Majority of the macrophages exhibit the “alternative/non-classic” subtype (Ly6C⁻CCR2^loCX3CR1^hi) and are characterized as anti-inflammatory at several weeks after ischemic stroke. M2 macrophages exhibit three distinct phenotypes based on their morphology. However, based on the inducers and a consensus collection of markers, M2 macrophages can be divided into four subtypes. The identification of macrophages by morphological or cellular markers remains contentious and confusing. (B) Despite the confusion of macrophage identification, overall M2 macrophages have been shown to contribute to the resolution of inflammation, efferocytosis, and angiogenesis.

Figure 4

Tregs play a central role in the immune cell-mediated nerve repair process. In addition to the resolution of inflammation, Tregs express interleukin (IL)-10 that contributes to the proliferation of neural stem cells (NSCs). Tregs also produce amphiregulin (AREG), which are bound to epidermal growth factor receptors on astrocytes and inhibit deleterious astrocytic reaction. Osteopontin (OPN) is also secreted by Tregs and induces the reparative phenotype of microglia, promoting oligodendrogenesis. Some cytokines have been reported to have effects on NSCs, and these factors have also been expressed in other types of T cells, suggesting that these T cells may also have potential effects on NSCs.