Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma

doi:10.1126/science.abf7844

GSTDTAP > 气候变化

DOI	10.1126/science.abf7844
	Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma
	Andrea Cugurra; Tornike Mamuladze; Justin Rustenhoven; Taitea Dykstra; Giorgi Beroshvili; Zev J. Greenberg; Wendy Baker; Zach Papadopoulos; Antoine Drieu; Susan Blackburn; Mitsuhiro Kanamori; Simone Brioschi; Jasmin Herz; Laura G. Schuettpelz; Marco Colonna; Igor Smirnov; Jonathan Kipnis
	2021-07-23
发表期刊	Science
出版年	2021
英文摘要	The meninges comprise three membranes that surround and protect the central nervous system (CNS). Recent studies have noted the existence of myeloid cells resident there, but little is known about their ontogeny and function, and whether other meningeal immune cell populations have important roles remains unclear (see the Perspective by Nguyen and Kubes). Cugurra et al. found in mice that a large proportion of continuously replenished myeloid cells in the dura mater are not blood derived, but rather transit from cranial bone marrow through specialized channels. In models of CNS injury and neuroinflammation, the authors demonstrated that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts. Similarly, Brioschi et al. show that the meninges host B cells that are also derived from skull bone marrow, mature locally, and likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a second population of age-associated B cells, which come from the periphery and may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Together, these two studies may inform future treatment of neurological diseases. Science , abf7844, abf9277, this issue p. [eabf7844][1], p. [eabf9277][2]; see also abj8183, p. [396][3] ### INTRODUCTION Myeloid cells are highly heterogeneous, with distinct ontogenies and immune functions. The diverse role of myeloid populations, including monocytes, macrophages, and neutrophils, in homeostasis of central nervous system (CNS) function is increasingly recognized. Brain borders, including the dura mater of the meninges, host a substantial pool of myeloid cells that mediate immune surveillance of the CNS. During injury and neuroinflammation, myeloid cells infiltrate the CNS and display heterogeneous functions from microglia, the CNS resident macrophages. Understanding myeloid ontogeny in CNS borders and in the CNS parenchyma under homeostasis and during perturbations is critical for our understanding of the basic mechanisms underlying immune responses in the diseased CNS and for the design of therapeutic approaches for neurological conditions associated with inflammation, such as injury, chronic neurodegenerative diseases, CNS infections, and brain tumors. ### RATIONALE Myeloid cells are critical contributors to CNS function, yet the origins of these cells at CNS borders and the routes of their migration into the CNS parenchyma under inflammatory or neurodegenerative conditions remain unclear. Under certain circumstances—for example, monocyte infiltration in experimental autoimmune encephalomyelitis (EAE) or after CNS injury—myeloid populations are playing protective and pathological roles. We rationalized that these heterogeneous functions may represent diverse cellular origins and sought to investigate the sources of myeloid cell infiltrates and the routes by which they access the injured or inflamed parenchyma. Channels connecting the skull bone marrow to the dura to allow neutrophil migration during stroke were previously described. Thus, we explored whether these channels and the skull bone marrow niche also allow for maintenance of the brain dural myeloid pool under homeostasis and in mouse models of CNS diseases. We further extended our observations to the vertebrae bone marrow niche as a potential source of myeloid cells for the spinal dura. ### RESULTS Using the parabiotic pairing of WT–UBC-GFP or CD45.1-CD45.2 mice that share blood circulation, we observed a substantial pool of monocytes and neutrophils in the brain and spinal cord dura that were not blood derived and had not arisen from tissue intrinsic progenitors or local proliferation. Using several approaches, including calvaria bone–flap transplantation and selective irradiation regimens with head or body shielding and bone marrow transfers, we found that these non–blood-derived myeloid cells had originated from skull and vertebrae bone marrow. We reconfirmed the existence of skull bone marrow–dura channels and described the presence of similar channels connecting spinal cord vertebrae bone marrow to spinal dura, allowing an anatomical route for constant myeloid migration from local bone marrow pools. After various CNS injury models, including spinal cord injury, EAE, and optic nerve crush, we showed that CNS-associated bone marrow contributes to parenchymal CNS infiltration. Using single-cell RNA sequencing, we demonstrated potentially nonredundant roles for blood and CNS bone marrow–derived monocytes infiltrating the spinal cord during spinal cord injury and EAE, with blood-derived cells displaying a more inflammatory and possibly pathogenic phenotype. ### CONCLUSION Our results show that bone marrow niches adjacent to the brain and spinal cord supply monocytes to the meninges under homeostasis and after CNS injury or neuroinflammatory disease. Moreover, we demonstrate that CNS border–derived myeloid cells can migrate through meningeal barriers into parenchyma under injurious and inflammatory conditions. CNS border–derived myeloid cells exhibit a less inflammatory and more regulatory phenotype when compared with their blood-derived counterparts in models of CNS injury and neuroinflammation. Thus, it is possible that these cells are playing critical roles in the regulation—and possibly attenuation—of immune responses in other contexts, such as CNS infections and brain tumors. Understanding the function of brain border–derived myeloid cells in CNS immune surveillance in physiology and pathology may lead to development of therapeutic avenues to treat neurological diseases. ![Figure][4] Myeloid cells from skull and vertebrae bone marrow supply brain borders and the CNS during health and disease. Under homeostasis, the dural meninges host a pool of monocytes derived from local bone marrow sources that can differentiate into tissue-resident macrophages. During CNS injury, bone marrow–derived monocytes can infiltrate CNS parenchyma from brain borders. The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells. [1]: /lookup/doi/10.1126/science.abf7844 [2]: /lookup/doi/10.1126/science.abf9277 [3]: /lookup/doi/10.1126/science.abj8183 [4]: pending:yes
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/334470
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Andrea Cugurra,Tornike Mamuladze,Justin Rustenhoven,et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma[J]. Science,2021.
APA	Andrea Cugurra.,Tornike Mamuladze.,Justin Rustenhoven.,Taitea Dykstra.,Giorgi Beroshvili.,...&Jonathan Kipnis.(2021).Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma.Science.
MLA	Andrea Cugurra,et al."Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma".Science (2021).