Bespoke brain immunity

doi:10.1126/science.abj8183

GSTDTAP > 气候变化

DOI	10.1126/science.abj8183
	Bespoke brain immunity
	Rita H. Nguyen; Paul Kubes
	2021-07-23
发表期刊	Science
出版年	2021
英文摘要	A primary defense strategy in response to infection or inflammation is to mobilize innate immune cells through the circulatory system to the affected organ. Patrolling monocytes and neutrophils constantly monitor healthy tissue and extravasate from vascular endothelium to infected or injured tissue through a stepwise mechanism ([ 1 ][1]). On page 409 of this issue, Cugurra et al. ([ 2 ][2]) demonstrate in a mouse model a pathway by which the central nervous system (CNS) bypasses this circulatory patrol system and supplies the meninges (the membranes that enclose the brain and spinal cord) with functionally distinct myeloid cells through channels that traverse the skull bone marrow. Moreover, on page 408 of this issue, Brioschi et al. ([ 3 ][3]) demonstrate that the meninges are also populated with B cells directly derived from skull marrow hematopoiesis. These studies show that the brain is an immunologically distinct organ that is surrounded by its own cadre of immune cells. ![Figure][4] Organ-specific immune niches The central nervous system is enclosed by the skull and vertebrae, the marrow of which provide a private source of immune cells that can invade the brain and spinal cord under pathological conditions through ossified vascular channels. Other organs harbor specialized immune cells in the tissue and spaces that surround them, such as specialized macrophages that can repair cardiac tissue after ischemia. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The skull consists of two thin plates of outer and inner cortical bone tables separated by the diploic space of cancellous bone. The diploic space contains the fatty marrow and is highly vascular, filled with veins that span from the outer and inner tables. Emissary veins cross from the scalp, through the skull, to the meninges overlying the brain. Thus, the brain is enclosed in a rich vascular network contained in the meninges and the skull. These vascular spaces have traditionally been thought to provide additional sites for cerebrospinal fluid resorption. However, recent animal studies have demonstrated that these skull-meninges connections have a much more dynamic role, and under pathological conditions such as stroke, they serve as highways for myeloid cells to quickly transmit from skull marrow to the brain parenchyma ([ 4 ][5]). Cugurra et al. expand these findings to demonstrate that even under homeostatic conditions, the skull marrow directly supplies myeloid cells to the meninges. These meningeal myeloid cells act as sentries of the brain, poised to respond to the first sign of perturbation. Indeed, Cugurra et al. went on to study CNS–bone marrow–derived myeloid cells versus blood-derived myeloid cells in mice under three different pathological conditions: autoimmune encephalomyelitis (EAE), spinal cord injury (SCI), and optic nerve crush injury. The authors observed that monocytes that infiltrated the spinal cord or optic nerve in these models were primarily derived from CNS-marrow, suggesting that the meningeal monocytes preferentially protect the organ that it borders. Furthermore, gene expression analysis between CNS-marrow–derived versus blood-derived infiltrating monocytes in EAE reveal that blood-derived monocytes were more enriched for proinflammatory pathways, suggesting differential roles for these monocytes in pathological conditions. Brioschi et al. also show that the skull marrow supplies the meninges with B cells in mice. These meningeal B cells mature in the dura and learn to recognize and tolerate CNS antigens. However, in aging mice, the meninges become populated with antigen-experienced, aged B cells derived from the peripheral circulation that have the potential to disrupt the balance of the distinct CNS immune milieu. This finding invites intriguing hypotheses for the pathophysiology of CNS autoimmune diseases such as multiple sclerosis, for which B cell depletion has shown therapeutic benefit ([ 5 ][6]). Cugurra et al. and Brioschi et al. suggest that the brain is distinct in having a direct bone marrow pipeline of immune cells to the borders of the brain (see the figure). Although other organs such as heart, lungs, and visceral organs do not have this selective pipeline, it is often forgotten that all these organs do have an organized structure or reservoir of immune cells at their borders. In 1906, the omentum, which covers the visceral organs, was referred to as “the policeman of the abdomen” because it attenuates peritonitis and improves surgical wound healing ([ 6 ][7]). Areas on the omentum called milky spots contain immune cells that can promote angiogenesis ([ 7 ][8]) and tissue repair ([ 8 ][9]). Fat-associated lymphoid clusters in the peritoneal, pericardial, and pleural cavity of mice are storage sites for lymphoid cells ([ 9 ][10]) and have been implicated in myocardial fibrosis after myocardial infarct (heart attack) ([ 10 ][11]). In addition, a distinct population of GATA-binding protein 6–positive (GATA6+) macrophages reside in all three major cavities, depend on retinoic acid for their identity, and retain their cavity gene expression signature regardless of whether they are in the peritoneal, pleural, or pericardial space ([ 11 ][12]). These cells accumulate rapidly at sites of organ injury and affect healing from the outside ([ 12 ][13]). Comparably, Cugurra et al. and Brioschi et al. illustrate that the brain and spinal cord harbor an exclusive pool of immune cells in the meninges that influence CNS diseases. Clearly, many organs have an immune presence localized to their borders, but the degree to which these cells are solicited to the parenchyma is unclear. The wealth of immune cells that surround various organs also raises the issue of immune cell recruitment. The canonical manner by which immune cells are recruited is through the vasculature and, in most cases, by extravasation from the postcapillary venules ([ 13 ][14]). However, Cugurra et al. , Brioschi et al. , and others ([ 4 ][5], [ 12 ][13]) have raised the possibility that immune cells could be recruited through the process of “invasion,” which involves migration into an organ from the perimeter, perhaps even by way of an avascular route. Having a pool of mature immune cells surrounding an organ provides a critical, immediately available reservoir of specific immune cells. For example, recruitment of monocytes from bone marrow to tissues where they become mature macrophages to initiate repair could take days, especially if new vasculature needs to be constructed. By contrast, a population of mature monocytes in the CNS, or mature GATA6+ macrophages in visceral cavities, are poised to instantly respond to brain, heart, or lung injury. The findings of Cugurra et al. and Brioschi et al. suggest that the blood-brain barrier does not necessarily need to be disrupted for meningeal immune cells to infiltrate the brain parenchyma. The clinical implications are numerous. For example, gliomas are primary brain tumors that are notoriously difficult to treat. Infiltrating monocytes have been shown to promote tumorigenesis ([ 14 ][15]). It would be fascinating to exploit the skull-meninges connections to influence myeloid cell chemotaxis as an immunotherapeutic option. Moreover, there is currently no medical treatment available for traumatic brain injury. Recent data show that myeloid cells promote vascular repair after traumatic brain injury ([ 15 ][16]). Perhaps the skull marrow myeloid cell reservoir can be harnessed as an immediate source of reparative cells. It remains unknown whether there are specific CNS signaling molecules that preferentially recruit meningeal immune cells over blood-derived cells. Is this also the case for visceral organs, heart, and lungs? Furthermore, the temporal dynamics of infiltration of CNS-marrow–derived versus blood-derived cells versus cavity immune cells needs to be explored and evaluated against disease progression. In surgical interventions, inadvertent removal of the border pericardium (during heart surgery), fusion of the pleural space (to limit effusions), craniotomy (removal of part of the skull), or durotomy (perforation of the dura mater meningeal membrane) can occur. What are the implications of these procedures for these cell niches and the physiological responses of an organ? The studies of Cugurra et al. and Brioschi et al. remind us that there is a vast amount of immunity that surrounds each organ with a coterie of immune cells with distinct phenotypes. In the case of the brain, it provides yet another specialized layer that should be considered in the context of the CNS. 1. [↵][17]1. C. Auffray et al ., Science 317, 666 (2007). [OpenUrl][18][Abstract/FREE Full Text][19] 2. [↵][20]1. A. Cugurra et al ., Science 373, eabf7844 (2021). [OpenUrl][21][Abstract/FREE Full Text][22] 3. [↵][23]1. S. Brioschi et al ., Science 373, eabf9277 (2021). [OpenUrl][24][Abstract/FREE Full Text][25] 4. [↵][26]1. F. Herisson et al ., Nat. Neurosci. 21, 1209 (2018). [OpenUrl][27][CrossRef][28][PubMed][29] 5. [↵][30]1. S. L. Hauser et al ., N. Engl. J. Med. 383, 546 (2020). [OpenUrl][31][CrossRef][32][PubMed][33] 6. [↵][34]1. R. Morison , BMJ 1, 76 (1906). [OpenUrl][35][FREE Full Text][36] 7. [↵][37]1. I. García-Gómez et al ., Neurol. Res. 27, 807 (2005). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334462
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Rita H. Nguyen,Paul Kubes. Bespoke brain immunity[J]. Science,2021.
APA	Rita H. Nguyen,&Paul Kubes.(2021).Bespoke brain immunity.Science.
MLA	Rita H. Nguyen,et al."Bespoke brain immunity".Science (2021).