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      Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage

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          Abstract

          Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH). Meningeal lymphatics have been reported to drain macromolecules and immune cells from CSF into cervical lymph nodes (CLNs). However, whether meningeal lymphatics are involved in clearing extravasated erythrocytes in CSF after SAH remains unclear. Here we show that a markedly higher number of erythrocytes are accumulated in the lymphatics of CLNs and meningeal lymphatics after SAH. When the meningeal lymphatics are depleted in a mouse model of SAH, the degree of erythrocyte aggregation in CLNs is significantly lower, while the associated neuroinflammation and the neurologic deficits are dramatically exacerbated. In addition, during SAH lymph flow is increased but without significant lymphangiogenesis and lymphangiectasia. Taken together, this work demonstrates that the meningeal lymphatics drain extravasated erythrocytes from CSF into CLNs after SAH, while suggesting that modulating this draining may offer therapeutic approaches to alleviate SAH severity.

          Abstract

          Extravasated erythrocytes in cerebrospinal fluid (CSF) contribute to the pathogenesis of subarachnoid haemorrhage (SAH). Here, the authors show that meningeal lymphatics drain extravasated erythorcytes and that blockage of this drainage aggravates SAH severity.

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          Most cited references 42

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          Interstitial dendritic cell guidance by haptotactic chemokine gradients.

          Directional guidance of cells via gradients of chemokines is considered crucial for embryonic development, cancer dissemination, and immune responses. Nevertheless, the concept still lacks direct experimental confirmation in vivo. Here, we identify endogenous gradients of the chemokine CCL21 within mouse skin and show that they guide dendritic cells toward lymphatic vessels. Quantitative imaging reveals depots of CCL21 within lymphatic endothelial cells and steeply decaying gradients within the perilymphatic interstitium. These gradients match the migratory patterns of the dendritic cells, which directionally approach vessels from a distance of up to 90-micrometers. Interstitial CCL21 is immobilized to heparan sulfates, and its experimental delocalization or swamping the endogenous gradients abolishes directed migration. These findings functionally establish the concept of haptotaxis, directed migration along immobilized gradients, in tissues.
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            Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues.

            Lymphocytes travel throughout the body to carry out immune surveillance and participate in inflammatory reactions. Their path takes them from blood through tissues into lymph and back to blood. Molecules that control lymphocyte recruitment into extralymphoid tissues are well characterized, but exit is assumed to be random. Here, we showed that lymphocyte emigration from the skin was regulated and was sensitive to pertussis toxin. CD4(+) lymphocytes emigrated more efficiently than CD8(+) or B lymphocytes. T lymphocytes in the afferent lymph expressed functional chemokine receptor CCR7, and CCR7 was required for T lymphocyte exit from the skin. The regulated expression of CCR7 by tissue T lymphocytes may control their exit, acting with recruitment mechanisms to regulate lymphocyte transit and accumulation during immune surveillance and inflammation.
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              Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1.

              Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.
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                Author and article information

                Contributors
                liangqianqian@shutcm.edu.cn
                YJwang8888@126.com
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 June 2020
                22 June 2020
                2020
                : 11
                Affiliations
                [1 ]ISNI 0000 0001 2372 7462, GRID grid.412540.6, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, ; 725 Wan-Ping South Road, 200032 Shanghai, China
                [2 ]ISNI 0000 0001 2372 7462, GRID grid.412540.6, Spine Institute, , Shanghai University of Traditional Chinese Medicine, ; 725 Wan-Ping South Road, 200032 Shanghai, China
                [3 ]ISNI 0000 0001 2372 7462, GRID grid.412540.6, School of Rehabilitation Science, , Shanghai University of Traditional Chinese Medicine, ; 1200 Cailun Road, 201203 Shanghai, China
                [4 ]ISNI 0000 0004 0369 313X, GRID grid.419897.a, Key Laboratory of Theory and Therapy of Muscles and Bones, , Ministry of Education (Shanghai University of Traditional Chinese Medicine), ; 1200 Cailun Road, 201203 Shanghai, China
                [5 ]ISNI 0000 0001 2372 7462, GRID grid.412540.6, Department of Anatomy, School of Basic Medicine, , Shanghai University of Traditional Chinese Medicine, ; 1200 Cailun Road, 201203 Shanghai, China
                [6 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, Department of Pathology and Laboratory Medicine and Center for Musculoskeletal Research, , University of Rochester Medical Center, ; 601 Elmwood Avenue, Rochester, NY 14642 USA
                [7 ]ISNI 0000 0004 1765 1045, GRID grid.410745.3, The International Education College, , Nanjing University of Chinese Medicine, ; 138 Xianlin Road, 210029 Nanjing, China
                [8 ]ISNI 0000 0000 8848 7685, GRID grid.411866.c, The Fourth Clinical Medical College, , Guangzhou University of Traditional Chinese Medicine, ; 232 Huandong Road, 510006 Guangdong, China
                Article
                16851
                10.1038/s41467-020-16851-z
                7308412
                32572022
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: National Natrural science foundation of China 81822050
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                © The Author(s) 2020

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