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      Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

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          Abstract

          Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.

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          Most cited references 32

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          Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

          Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.
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            Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool.

            In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor-dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.
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              The origin and development of nonlymphoid tissue CD103+ DCs

              CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103+ DCs are related to lymphoid organ CD8+ DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103+ DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c+MHCII+ cells in tissues, which is CD103−CD11b+, is heterogenous and depends on both Flt3 and MCSF-R. Our results reveal that nonlymphoid tissue CD103+ DCs and lymphoid organ CD8+ DCs derive from the same precursor and follow a related differentiation program.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                17 May 2014
                08 December 2013
                January 2014
                01 July 2014
                : 17
                : 1
                : 131-143
                Affiliations
                [1 ]Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02112
                [2 ]Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
                [3 ]Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada
                [4 ]Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
                [5 ]Department of Immunology, Cleveland Clinic, Cleveland, Ohio, USA
                Author notes
                [* ]Corresponding authors: Oleg Butovsky, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur HIM 730, Boston, MA 02115, Tel: +1-617-525-5300, Fax: +1-617-525-5252, obutovsky@ 123456rics.bwh.harvard.edu or Howard L. Weiner, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur HIM 730, Boston, MA 02115, Tel: +1-617-525-5300, Fax: +1-617-525-5252, hweiner@ 123456rics.bwh.harvard.edu
                Article
                NIHMS560033
                10.1038/nn.3599
                4066672
                24316888
                Categories
                Article

                Neurosciences

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