Abstract

Microglia in the brain and macrophages in peripheral organs are cell types responsible for immune response to challenges. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme of the tryptophan pathway that is expressed in the brain. The higher activity of IDO1 in response to immune challenge has been implicated in behavioral disorders. The impact of IDO1 depletion on the microglia transcriptome has not been studied. An investigation of the transcript networks in the brain microglia from IDO1-knockout (IDO1-KO) mice was undertaken, relative to peripheral macrophages and to wild-type (WT) mice under unchallenged conditions. Over 105 transcript isoforms were differentially expressed between WT and IDO1-KO within cell type. Within microglia, Saa3 and Irg1 were over-expressed in IDO1-KO relative to WT. Within macrophages, Csf3 and Sele were over-expressed in IDO1-KO relative to WT. Among the genes differentially expressed between strains, enriched biological processes included ion homeostasis and ensheathment of neurons within microglia, and cytokine and chemokine expression within macrophages. Over 11,110 transcript isoforms were differentially expressed between microglia and macrophages and of these, over 10,800 transcripts overlapped between strains. Enriched biological processes among the genes over- and under-expressed in microglia relative to macrophages included cell adhesion and apoptosis, respectively. Detected only in microglia or macrophages were 421 and 43 transcript isoforms, respectively. Alternative splicing between cell types based on differential transcript isoform abundance was detected in 210 genes including Phf11d, H2afy, and Abr. Across strains, networks depicted a predominance of genes under-expressed in microglia relative to macrophages that may be a precursor for the different response of both cell types to challenges. The detected transcriptome differences enhance the understanding of the role of IDO1 in the microglia transcriptome under unchallenged conditions.

Highlights

  • During neuroinflammation microglia cells release pro-inflammatory cytokines that are associated with increased activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that catalyzes tryptophan within the kynurenine pathway

  • Differential expression between these immune cells on a number of candidate genes has been reported including: genes coding for scavenger receptors [2], Toll-like receptors (Tlrs) and chemokine receptors [3], Fc receptors [4], antimicrobial peptides [5], purinergic receptors P2y and P2x [6], interferon-inducible transmembrane (Ifitms) and sialic acid—binding immunoglobulin lectins (Siglecs) [7,8]

  • This dysregulation could result in the over-expression of genes that link metabolism and immune response as a compensatory mechanism to regulate the immune system under potential challenge conditions

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Summary

Introduction

During neuroinflammation microglia cells release pro-inflammatory cytokines that are associated with increased activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that catalyzes tryptophan within the kynurenine pathway. Despite the shared overall role of brain microglia and peripheral macrophages, differences in origin, morphology and gene expression between these immune cells have been linked to distinct impact on a number of biological processes. Differential expression between these immune cells on a number of candidate genes has been reported including: genes coding for scavenger receptors [2], Toll-like receptors (Tlrs) and chemokine receptors [3], Fc receptors [4], antimicrobial peptides [5], purinergic receptors P2y and P2x [6], interferon-inducible transmembrane (Ifitms) and sialic acid—binding immunoglobulin lectins (Siglecs) [7,8]. No comparison of the brain microglia and peripheral macrophage transcriptome between wild type (WT) and IDO1-KO mice has been reported

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