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Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia
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
Distinct biomarkers as prognostic in chronic lymphocytic leukemia patients treated with alvocidib and lenalidomide as single agents or combination regimens thereof.
Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Differential Roles Of Microglia And Monocytes In The Inflamed Central Nervous System
In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.WoSScopu