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      Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke

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          Abstract

          Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes to the macrophage phenotype during inflammation. Here, we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4-deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.

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          A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.

          Shiaoching Gong, Chen Zheng, Martin Doughty … (2003)
          The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.
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            Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

            Bahareh Ajami, Jami Bennett, Charles Krieger … (2007)
            Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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              Neuroinflammation: friend and foe for ischemic stroke

              Richard L. Jayaraj, Sheikh Azimullah, Rami Beiram … (2019)
              Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9809671
                Journal ID (pubmed-jr-id): 21092
                Journal ID (nlm-ta): Nat Neurosci
                Journal ID (iso-abbrev): Nat. Neurosci.
                Title: Nature neuroscience
                ISSN (Print): 1097-6256
                ISSN (Electronic): 1546-1726
                Publication date Nihms-submitted: 14 September 2020
                Publication date (Electronic): 10 February 2020
                Publication date (Print): March 2020
                Publication date PMC-release: 29 September 2020
                Volume: 23
                Issue: 3
                Pages: 351-362
                Affiliations
                [1: ]Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
                [2: ]Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, USA.
                [3: ]Developmental Biology of the Innate Immune System, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
                [4: ]Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
                [5: ]PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany
                [6: ]Lippe General Hospital, Department of Neurology, Lemgo, Germany
                Author notes

                Author contributions

                E.M., F.G., and R.S. conceived the project. P.A.K., K.H., A.L., E.M., D.S., F.S., and Y.W. performed experiments. A.H., P.A.K., K.K., E.M., R.S., T.U., and YW analyzed data. R.S and Y.W. designed figures. F.G., E.M., J.L.S, and R.S. supervised experiments and data analysis. C.R. helped to establish stroke models. E.M., F.G., and R.S. wrote the manuscript.

                [$]

                The authors contributed equally to this work.

                [* ]Correspondence: Ralf Stumm, ralf.stumm@ 123456med.uni-jena.de ; Elvira Mass, emass@ 123456uni-bonn.de , and Frederic Geissmann, geissmaf@ 123456mskcc.org
                Article
                Accession ID: PMC7523735 Pmcid ID: PMC7523735 Pmc-uid ID: 7523735 Manuscript ID: nihpa1622479
                DOI: 10.1038/s41593-020-0585-y
                PMC ID: 7523735
                PubMed ID: 32042176
                SO-VID: 26d90721-546d-41e1-824a-ec2e2d0a604f
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