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Selected TLR7/8 agonist and type I interferon (IFN-?) cooperatively redefine the microglia transcriptome.


ABSTRACT: BACKGROUND:Microglia, the primary immune cells of the central nervous system, exerts multiple functions to mediate many neurological diseases. Upon any detection of invading pathogen products (e.g., TLR agonists) or host-released signaling factors (e.g., interferon/IFN), these cells undergo an activation process to release large numbers of inflammatory substances that participate in inflammation and homeostasis. The profound effects of inflammation associated with TLR7/8 agonist Resiquimod (R848) and type 1 interferon (e.g., IFN-?)-induced macrophage and dendritic cell activation on biological outcomes have long been recognized. However, the underlying mechanisms are not well defined in microglial cells. METHODS:The present study investigated the molecular signatures of microglia and identified genes that are uniquely or synergistically expressed in R848-, IFN-?- or R848 with IFN-?-treated primary microglial (PM) cells. We used RNA-sequencing, quantitative real-time PCR, and bioinformatics approaches to derive regulatory networks that control the transcriptional response of PM to R848, IFN-? and R848 with IFN-?. RESULTS:Our approach revealed that the inflammatory response in R848 with IFN-?-treated PM is faster and more intense than that in R848 or IFN-?-treated PM in terms of the number of differentially expressed genes and the magnitude of induction/repression. In particular, our integrative analysis enabled us to suggest the regulatory functions of TFs, which allowed the construction of a network model that explains how TLR7/8 and IFN-?-sensing pathways achieve specificity. CONCLUSION:In conclusion, the systematic approach presented herein could be important to the understanding microglial activation-mediated molecular signatures induced by inflammatory stimuli related to TLR7/8, IFN-? or co-signaling, and associated transcriptional machinery of microglial functions and neuroinflammatory mechanisms.

SUBMITTER: Khatun MR 

PROVIDER: S-EPMC7087773 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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RETRACTED ARTICLE: Selected TLR7/8 agonist and type I interferon (IFN-α) cooperatively redefine the microglia transcriptome.

Khatun Mst Reshma MR   Arifuzzaman Sarder S  

Inflammopharmacology 20200717


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