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MAPKs control the expression of a novel gene set that defines de activation of human anti-inflammatory macrophages

ABSTRACT: LPS treatment is considered as the paradigmatic stimulus for acquisition of the classical macrophage polarization/activation state. However, this definition does not take into account the influence that other macrophage differentiating/priming factors might have on the LPS response. In spite of the pathophysiological relevance of the response of M-CSF-dependent anti-inflammatory human macrophages (M-MØ) to endogenous and pathogenic stimuli, detailed analysis of the gene signature of activated anti-inflammatory M-CSF-dependent macrophages remained to be determined. We have now compared the early transcriptional signatures of human GM-MØ and M-MØ in response to macrophage-activating agents and identified a unique gene set acquired upon activation of anti-inflammatory M-MØ.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99056 | GEO | 2017/09/22

SECONDARY ACCESSION(S): PRJNA387152

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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MAPKs control the expression of a novel gene set that defines de activation of human anti-inflammatory macrophages

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