Although the brain was once thought to be immunoprivileged, it is now recognized that a major immune niche exists along the borders of the brain, created by the infiltration of immune cells into the choroid plexus, meninges, and spinal cord. Masu. This occurs in the absence of inflammation, and in addition to its role in disease pathology, [1]these immune niches are important for brain development [2] and homeostasis [3]. Over the past two decades, researchers have demonstrated long-range communication between the brain and the immune system. [4] Through drainage of cerebrospinal fluid (CSF), immune cells flow into the deep cervical lymph nodes through the meningeal lymphatic vessels. More recent evidence indicates that the cranial marrow plays an important role in central nervous system (CNS) immune surveillance in normal physiology and in response to injury. [5]. Furthermore, many cytokines and proinflammatory signaling pathways are thought to be involved in hypertension and other cardiovascular diseases (CVD). [6]. Therefore, the brain is not protected from the immune system, but maintains a dynamic and functional relationship with the immune system for brain and body homeostatic regulation.

General neuroinflammation is important in CVD pathology; [7], a comprehensive understanding of cell-specific changes to the neuroimmune niche during CVD is lacking. Here we outline the main functions of these neuroimmune niches and their role in CVD (Figure 1). 1). However, the neural control of the peripheral immune system has been extensively reviewed elsewhere and will not be discussed here. [8‐10].

Although microglia are the most abundant immune cells in the brain, both microglia and astrocytes serve as the main immunocompetent cells within the CNS parenchyma.Both cell types are capable of cytokine release [11, 12]phagocytose cell debris and toxic aggregates [13‐15]and expression of major histocompatibility complex class II (MHCII) for antigen presentation. [16, 17]. Indeed, these glial cells exploit their extensive arborization processes to monitor their surrounding neuronal and vascular environment. Specifically, microglia monitor the brain by extending and retracting their processes. [18] Meanwhile, astrocytes form syncytia with neighboring astrocytes to monitor neurotransmission. [19] vascular tension and [20]. Removal of toxic protein aggregates requires mutual communication between microglia and astrocytes. For example, co-cultures of microglia and astrocytes remove amyloid beta (Aβ) and α-synuclein more effectively than cultures of either alone. [21]. Tunneling nanotubes mediate direct physical communication between microglia and astrocytes and facilitate the removal of protein aggregates from astrocytes by microglia. [21]. This reciprocal communication is necessary for brain waste removal, as the accumulation of toxic protein aggregates in the brain is associated with CVD and dementia. [22].

Adjacent to the parenchyma, the brain is equipped with specialized subsets of myeloid cells that reside in the choroid plexus, leptomeninges, and perivascular spaces. These three macrophage populations are collectively known as brain border-associated macrophages (BAM). BAMs arise from the same yolk sac-derived erythromyeloid progenitors as microglia, but the two cell types diverge by embryonic day 12.5. [23].

BAMs in the leptomeningeal and perivascular spaces establish stable self-renewing populations with minimal exchange from blood-derived cells, whereas macrophages in the choroid plexus maintain continuous engagement with peripheral hematopoietic stem cells (HSCs). Receive an exchange. [24]. Recent studies have found that in the absence of disease, BAM plays a major role in regulating arterial vasomotion, extracellular matrix remodeling, and CSF flow. [25••]. Although there is still much research to be done regarding the homeostatic effects of BAM, there is evidence supporting the role of BAM in CVD, including cerebral amyloid angiopathy. [26•] and hypertension-induced neurovascular dysfunction. [27]. Furthermore, BAM was recently identified as the main causative agent of Aβ immunotherapy-induced microbleeds. [28•].

The dura mater is the outermost and thickest layer of the meninges and serves as the primary site of lymphatic drainage of CSF. [29]. Dural immune cells, particularly sinus-associated antigen-presenting cells, are uniquely positioned to detect brain-derived antigens found in the CSF flowing through the dural sinuses. [30••].Functional dural lymphatic vessels [31] Drains these brain-derived antigens and immune cells to deep cervical lymph nodes. [32]. The dural neuroimmune niche is composed of innate and adaptive immune cells that are highly heterogeneous in both cellular composition and spatial distribution. Although dominated by macrophages, a wide variety of immune cells are found throughout the dura, including neutrophils, B cells, T cells, natural killer cells, and dendritic cells. [30••]. These immune cells are spatially localized into different subcompartments depending on their function. For example, dural macrophages are closely associated with dural blood vessels. [33]; T cells are primarily located around the dural sinuses. [30••]and pre-, pre-, immature, and mature B cells are found adjacent to and within the blood vessels and lymphatic vessels of the dura mater. [34•, 35].Fenestration of dural vessels allows the majority of dural immune cells to be transported from the periphery [36]containing IgA-producing plasma cells that are educated in the intestine and transported to the meninges to prevent CNS infection by blood pathogens [37].

Research over the past five years has demonstrated the existence of a direct channel between the dura mater and the craniomedullary membrane. [38••, 39••, 40••].Discovery of a bone marrow channel from the dura mater to the skull suggests that brain-derived antigens in the CSF may influence HSC proliferation and immune cell function in the cranial bone marrow [40••, 41•]. In particular, the cranial marrow is known to supply myeloid cells such as monocytes, neutrophils, dendritic cells, and macrophages to the dura mater. [38••] as well as B cells and B cell progenitors. [35]. These recent discoveries are paving the way for future discoveries, but much remains to be discovered. For example, the cues that modulate functional communication between the dura mater and craniomedullary mater, particularly the effects of disease on this communication, require further investigation.

In addition to CVD, hypertension is a major risk factor for dementia and cognitive decline. In the Ang II hypertensive model, BAM was the major source of ROS production, resulting in reduced neurovascular coupling and ultimately leading to cognitive impairment [27]. Recently, we demonstrated in a DOCA salt model of hypertension that dural T cell-derived IL-17 causes ROS production in the BAM via IL-17RA, which impairs neurovascular coupling and also leads to cognitive impairment. [102].Of note, in both studies, BAM depletion [27] or IL-17 T cells [102] Cognitive impairment recovered.These and other findings [26•, 98•] This provides the basis for future research to focus on the mechanisms underlying the negative effects on neural function resulting from peripheral brain border immune surveillance, ultimately contributing to cognitive impairment and dementia.

Given the newly discovered relationship between the dura mater and cranial marrow, future studies should investigate hypertension-induced changes to cranial marrow-derived immune cell populations and cytokine profiles. As mentioned above, dural and cranial bone marrow communication has only been studied in stroke models and remains poorly understood in CVD. Given the important contribution of her CVD to cognitive impairment and dementia, this neuroimmune niche cannot afford to remain unexplored. We recently discovered that intradural γδT17 cells mediate neurovascular and cognitive impairment in DOCA salt hypertension. [102]IL-17 produced in the dura then entered the CSF through disruption of the arachnoid barrier. [102]. This discovery identified a new entry route for peripheral molecules such as Ang II into the CNS.

CVD can also affect the relationship between microglia and astrocytes, which contributes to cognitive impairment. Here, we have discussed the individual roles of astrocytes and microglia in increasing blood pressure. However, the two cell types are inextricably linked, as they rarely function without the other, and their relationship is often described as a double-edged sword. One hypothesis is that sustained microglial activation in response to nerve injury triggers the release of inflammatory cytokines, leading to neurotoxic astrocyte reactivity. [104]. Further research is needed to elucidate how the bidirectional relationship between astrocytes and microglia exacerbates CVD and contributes to brain end-organ damage in chronic diseases such as hypertension. As a first step, we should leverage existing single-cell RNA-seq datasets to investigate this communication using inferential analyzes such as CellChat. [105].

The neuroimmune niches discussed in this review provide a new and interesting focus for both preclinical and clinical researchers. Importantly, the function of these neuroimmune niches in regulating brain homeostatic functions beyond immunity needs to be considered. For example, single-nuclear RNA-seq studies revealed that the choroid plexus epithelium expresses high levels of components of the renin-angiotensin system. [106••].Given the low brain expression of renin [107]the recent discovery of renin-expressing cells in the choroid plexus [106••] It may support local production of Ang II in the brain. Bridging the gap between known and as yet unidentified knowledge is important to reduce the negative impact of CVD on a global scale.