Dataset Information

Identification of Aryl Hydrocarbon Receptor (AhR) as a Functional Target that Enhances Astrocytic ApoE Secretion

ABSTRACT: We discovered a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Using chemoproteomics, photoaffinity probes, KINOMEscan analysis, and siRNA knockdowns, we identified the aryl hydrocarbon receptor (AhR), a transcription factor not previously linked to ApoE secretion, as the primary target. AhR antagonism was confirmed to increase ApoE secretion through a panel of agonists/antagonists and genetic knockdown. While chronic AhR inhibition is unsuitable for Alzheimer's treatment due to peripheral effects, these findings highlight AhR as a modulator of ApoE secretion and a pathway worth further exploration. There is two datasets deposited for this project. One dataset was generated through affinity chromatography enrichment, and the second dataset was generated through photo-affinity chromatography enrichment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Brain Cancer

SUBMITTER: Bekim Bajrami

LAB HEAD: Kirk Donovan

PROVIDER: PXD071908 | Pride | 2026-01-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	OE1_20220817_S_KD1_ApoE_PhotoAffinity_BIO-2251_Exp03_10000nM_01_007.mzML	Mzml
	OE1_20220817_S_KD1_ApoE_PhotoAffinity_BIO-2251_Exp03_10000nM_01_007.raw	Raw
	OE1_20220817_S_KD1_ApoE_PhotoAffinity_BIO-2251_Exp03_10000nM_02_014.mzML	Mzml
	OE1_20220817_S_KD1_ApoE_PhotoAffinity_BIO-2251_Exp03_10000nM_02_014.raw	Raw
	OE1_20220817_S_KD1_ApoE_PhotoAffinity_BIO-2251_Exp03_10000nM_03_021.mzML	Mzml

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Project description:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a broad range of target genes involved in the xenobiotic response, cell cycle control and circadian rhythm. AhR is constitutively expressed in macrophages, acting as key regulator of cytokine production. While proinflammatory cytokines, i.e., IL-1β, IL-6, IL-12, are suppressed through AhR activation, anti-inflammatory IL-10 is induced. However, the underlying mechanisms of those effects and the importance of the specific ligand structure are not yet completely understood. Therefore, we have compared the global gene expression pattern in activated murine bone marrow-derived macrophages (BMMs) subsequently to exposure with either benzo[a]pyrene (BaP) or indole-3-carbinol (I3C), representing xenobiotic vs. nutritional AhR ligands, respectively, by means of mRNA sequencing. AhR dependency of observed effects was proved using BMMs from AhR-knockout mice. In total, more than 1,000 differentially expressed genes (DEGs) could be mapped, covering a plethora of AhR-modulated effects on basal cellular processes, i.e., transcription and translation, but also immune functions, i.e., antigen presentation, cytokine production, and phagocytosis. Among DEGs were genes that are already known to be regulated by AhR, i.e., Irf1, Ido2, and Cd84. However, we identified DEGs not yet described to be AhR-regulated in macrophages so far, i.e., Slpi, Il12rb1, and Il21r. All six genes likely contribute to shifting the macrophage phenotype from proinflammatory to anti-inflammatory. The majority of DEGs were specific for BaP but not affected through I3C exposure, probably due to higher AhR affinity of BaP in comparison to I3C. Mapping of known aryl hydrocarbon response element (AHRE) sequence motifs in identified DEGs revealed more than 200 genes not possessing any AHRE, and therefore being not eligible for canonical regulation. Bioinformatic approaches modeled a central role of type I and type II interferons in the regulation of those genes. Additionally, RT-qPCR and ELISA confirmed a BaP- and AhR-dependent expressional induction and AhR-dependent secretion of IFN-γ, suggesting a potentially novel auto- or paracrine activation pathway of macrophages.

Dataset Information

Identification of Aryl Hydrocarbon Receptor (AhR) as a Functional Target that Enhances Astrocytic ApoE Secretion

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