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      Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage

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          Abstract

          Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood–brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

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          Microglial and macrophage polarization—new prospects for brain repair.

          Xiaoming Hu, Rehana Leak, Yejie Shi … (2015)
          The traditional view of the adult brain as a static organ has changed in the past three decades, with the emergence of evidence that it remains plastic and has some regenerative capacity after injury. In the injured brain, microglia and macrophages clear cellular debris and orchestrate neuronal restorative processes. However, activation of these cells can also hinder CNS repair and expand tissue damage. Polarization of macrophage populations toward different phenotypes at different stages of injury might account for this dual role. This Perspectives article highlights the specific roles of polarized microglial and macrophage populations in CNS repair after acute injury, and argues that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes. Breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.
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            Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats.

            Alison Willing, Y. Li, Wei Chen … (2001)
            Human umbilical cord blood cells (HUCBC) are rich in stem and progenitor cells. In this study we tested whether intravenously infused HUCBC enter brain, survive, differentiate, and improve neurological functional recovery after stroke in rats. In addition, we tested whether ischemic brain tissue extract selectively induces chemotaxis of HUCBC in vitro. Adult male Wistar rats were subjected to transient (2-hour) middle cerebral artery occlusion (MCAO). Experimental groups were as follows: group 1, MCAO alone (n=5); group 2, 3x10(6) HUCBC injected into tail vein at 24 hours after MCAO (n=6) (animals of groups 1 and 2 were killed at 14 days after MCAO); group 3, MCAO alone (n=5); group 4, MCAO injected with PBS at 1 day after stroke (n=8); and group 5, 3x10(6) HUCBC injected into tail vein at 7 days after MCAO (n=5). Rats of groups 3, 4, and 5 were killed at 35 days after MCAO. Behavioral tests (rotarod and Modified Neurological Severity Score [mNSS]) were performed. Immunohistochemical staining was used to identify cells derived from HUCBC. Chemotactic activity of ischemia brain tissue extracts toward HUCBC at different time points was evaluated in vitro. Treatment at 24 hours after MCAO with HUCBC significantly improved functional recovery, as evidenced by the rotarod test and mNSS (P<0.05). Treatment at 7 days after MCAO with HUCBC significantly improved function only on the mNSS (P<0.05). Some HUCBC were reactive for the astrocyte marker glial fibrillary acidic protein and the neuronal markers NeuN and microtubule-associated protein 2. In vitro, significant HUCBC migration activity was present at 24 hours after MCAO (P<0.01) compared with normal brain tissue. Intravenously administered HUCBC enter brain, survive, migrate, and improve functional recovery after stroke. HUCBC transplantation may provide a cell source to treat stroke.
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              Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.

              Oleg Butovsky, Shafiuddin Siddiqui, Galina Gabriely … (2012)
              Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cereb Blood Flow Metab
                Journal ID (iso-abbrev): J. Cereb. Blood Flow Metab
                Journal ID (publisher-id): JCB
                Journal ID (hwp): spjcb
                Title: Journal of Cerebral Blood Flow & Metabolism
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0271-678X
                ISSN (Electronic): 1559-7016
                Publication date (Electronic): 1 January 2016
                Publication date (Print): July 2017
                Volume: 37
                Issue: 7
                Pages: 2383-2395
                Affiliations
                [1 ]Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
                [2 ]Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, USA
                [3 ]Department of Neurology, Yale University School of Medicine, New Haven, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                [*]Fu-Dong Shi, Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China. Email: fshi@ 123456tmu.edu.cn
                Article
                Publisher ID: 10.1177_0271678X16666551
                DOI: 10.1177/0271678X16666551
                PMC ID: 5482387
                PubMed ID: 27596835
                SO-VID: 7e6b8bef-93e5-4075-9ced-5dfa9f05e2ae
                Copyright © © The Author(s) 2016
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 15 May 2016
                Date revision received : 29 July 2016
                Date accepted : 4 August 2016
                Categories
                Subject: Original Articles

                ScienceOpen disciplines: Neurosciences
                Keywords: colony stimulating factor 1 receptor inhibitor,intracerebral hemorrhage,brain edema,microglia,inflammation
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: colony stimulating factor 1 receptor inhibitor, intracerebral hemorrhage, brain edema, microglia, inflammation

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