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C-X-C chemokine receptor 4 ablation-driven transcriptional changes in monocyte-derived macrophage in response to lipopolysaccharide

ABSTRACT: Purpose: Next-Generation Sequencing (NGS) RNA was subjected to analysis genome-wide expression. The goals of this study are to identify differentially expressed genes in CXCR4 knockout macrophages compared to CXCR4-expressed macrophages. Methods: Total RNA of macrophage transfected with CXCR4 siRNA (MΦsiCXCR4) or siRNA negative control (MΦsiNC), then, stimulated with 100ng/ml lipopolysaccharide (LPS) for 12 hours. Preparation of library and sequencing of transcriptome was performed by Illumina NovaSeq 6000. Results: A large number of differentially expressed genes were screened by high-throughput sequencing at the genome-wide level using RNA-Seq technology. Loss of CXCR4 in bone-marrow-derived macrophages results in attenuated pro-inflammatory cytokine and decorin production under LPS stimulation compared to control macrophages. Conclusions: Our study reveals that CXCR4 orchestrated the pro-inflammatory cytokine and decorin production in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE182050 | GEO | 2023/08/06

REPOSITORIES: GEO

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Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.

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C-X-C chemokine receptor 4 ablation-driven transcriptional changes in monocyte-derived macrophage in response to lipopolysaccharide

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