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Autonomous TNF is critical for monocyte survival in steady state and inflammation in vivo

ABSTRACT: Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are upregulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such the spinal cord during experimental autoimmune encephalomyelitis (EAE). Using competitive in vitro and in vivo assays, we show here that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes / macrophages, but not in microglia delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE94546 | GEO | 2017/04/19

SECONDARY ACCESSION(S): PRJNA371454

REPOSITORIES: GEO

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Project description:Neural progenitor cells (NPCs) have regenerative capabilities that are activated during inflammation. By measuring the global transcriptome and performing functional studies, we aimed at elucidating if and how NPCs from the non-germinal niche of the spinal cord differ from germinal niche NPCs, here represented by the subventricular zone (SVZ) NPCs. Moreover, we investigated how these cells are affected by chronic inflammation modeled by Experimental Autoimmune Encephalomyelitis (EAE). NPCs were isolated and propagated from the SVZ and cervical, thoracic and caudal regions of the spinal cord from healthy rats and rats subjected to EAE. Using Affymetrix microarray analyses, the global transcriptome was measured in the different NPC populations both in undifferentiated and differentiated cultures. These analyses were paralleled by differentiation studies and quantitative RT-PCR of differentiation-specific genes. In NPCs isolated from healthy rats, transcriptional and functional analyses revealed a higher neurogenic potential in SVZ-derived NPCs compared to spinal cord NPCs. The neurogenicity of spinal cord NPCs was increased by exposure to the inflammatory environment. Concurrently, their gliogenicity was decreased which was supported by a decreased expression of glial differentiation signature genes and related signaling pathways. Differentiation analyses showed that spinal cord NPCs from EAE rats generated fewer oligodendrocytes and astrocytes than NPCs isolated from healthy controls. 54 samples were analysed. The transcriptome of NPCs isolated from healthy rats or rats with EAE was measured. The NPCs were isolated from the SVZ and the cervical, thoracic and caudal parts of the spinal cord. Pair wise student t-test analysis between the 3 EAE replicates and naive controls for each respective tissue type was performed. Genes with a signal value above the cut-off of 50 and with FDR M-bM-^IM-$ 5% and a foldchange of M-bM-^IM-%1.2 or M-bM-^IM-$-1.2 were selected for further analysis.

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Autonomous TNF is critical for monocyte survival in steady state and inflammation in vivo

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