The regulatory landscape of macrophage interferon signaling in inflammation

Siebeler, Ricky; Winther, Menno P.J. de; Hoeksema, Marten A.

doi:10.1016/j.jaci.2023.04.022

Cited by 11 publications

(5 citation statements)

References 182 publications

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“…Macrophages play a crucial role in the innate immune response as they are key regulators of the IFN and IL-27 system, orchestrating and enhancing IFN- and IL-27-dependent antiviral responses in both infectious and autoinflammatory diseases ( 25 , 58 – 60 ).…”

Section: Resultsmentioning

confidence: 99%

Interleukin 27, like interferons, activates JAK-STAT signaling and promotes pro-inflammatory and antiviral states that interfere with dengue and chikungunya viruses replication in human macrophages

Valdés-López,

Hernández-Sarmiento,

Tamayo-Molina

et al. 2024

Front. Immunol.

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Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggesting that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. To address this question, we conducted a comparative analysis of the transcriptomic profiles of human monocyte-derived macrophages (MDMs) exposed to IL-27 and those exposed to recombinant human IFN-α, IFN-γ, and IFN-λ. We utilized bioinformatics approaches to identify common differentially expressed genes between the different transcriptomes. To verify the accuracy of this approach, we used RT-qPCR, ELISA, flow cytometry, and microarrays data. We found that IFNs and IL-27 induce transcriptional changes in several genes, including those involved in JAK-STAT signaling, and induce shared pro-inflammatory and antiviral pathways in MDMs, leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs)Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response. Given this similarity, we propose that IL-27 could be classified as a distinct type of IFN, possibly categorized as IFN-pi (IFN-π), the type V IFN (IFN-V).

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Section: Resultsmentioning

confidence: 99%

Interleukin 27, like interferons, activates JAK-STAT signaling and promotes pro-inflammatory and antiviral states that interfere with dengue and chikungunya viruses replication in human macrophages

Valdés-López,

Hernández-Sarmiento,

Tamayo-Molina

et al. 2024

Front. Immunol.

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“…The biological functions of type I IFNs are extremely divergent (and sometimes opposing) in a contextdependent manner [26]. Unlike IFN-γ, which primes macrophages to a heightened proin ammatory status [42], IFN-α/β produce dichotomous effects in macrophages, forming a regulatory circuit able to reprogram macrophages to promote both in ammation and resolution [27]. For example, type I IFNs could facilitate proin ammatory macrophage activation by controlling LPS-induced IL-12 expression [43].…”

Section: Discussionmentioning

confidence: 99%

“…The above bioinformatics results pointed to the potential involvement of signalling pathways via pattern recognition receptors [25] in the biological effects of AP, including toll-like receptors (TLRs), NLRs and RLRs. Interestingly, it was found that the relevant genes enriched in these clusters converged to the type I IFN signalling network [26,27]. Speci cally, in LPS-challenged cells, AP downregulated the mRNA levels of an array of type I IFN responsive genes, including 4 of the 2'-5' oligoadenylate synthetase (OAS) family members, 5 of the interferon activated gene 200 (IFI200/HIN-200) family members, 4 of the interferoninduced protein with tetratricopeptide repeats (IFIT) family members, interferon-inducible GTPase 1 (IIGP1), interferon regulatory factor 7 (IRF7), TLR3, MX dynamin-like GTPase 1 (MX1), interferon regulatory factor 7/8 (IRF7/IRF8), interferon-stimulated protein (ISG20), interferon-induced protein 44 (IFI44), DEXH box polypeptide 58 (DHX58), and DExD/H box helicase 60 (DDX60) [26][27][28][29][30][31].…”

Section: Regulation Of the Type I Ifn Pathway By Apmentioning

confidence: 99%

“…Interestingly, it was found that the relevant genes enriched in these clusters converged to the type I IFN signalling network [26,27]. Speci cally, in LPS-challenged cells, AP downregulated the mRNA levels of an array of type I IFN responsive genes, including 4 of the 2'-5' oligoadenylate synthetase (OAS) family members, 5 of the interferon activated gene 200 (IFI200/HIN-200) family members, 4 of the interferoninduced protein with tetratricopeptide repeats (IFIT) family members, interferon-inducible GTPase 1 (IIGP1), interferon regulatory factor 7 (IRF7), TLR3, MX dynamin-like GTPase 1 (MX1), interferon regulatory factor 7/8 (IRF7/IRF8), interferon-stimulated protein (ISG20), interferon-induced protein 44 (IFI44), DEXH box polypeptide 58 (DHX58), and DExD/H box helicase 60 (DDX60) [26][27][28][29][30][31]. Given the evidence showing that activation of both type I and type II IFN signalling might be implicated in the pathogenesis of atherosclerosis [32][33][34][35], we then speci cally analysed the effects of AP on the type I IFN response.…”

Section: Regulation Of the Type I Ifn Pathway By Apmentioning

confidence: 99%

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Inhibition of type I interferon signalling is involved in the anti-atherogenic effects of Andrographis paniculata

Liu,

Alsherbiny

et al. 2024

Preprint

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Andrographis paniculata (Burm. f.) Wall. ex Nees (AP) is a medicinal herb widely used in many Asian countries. Andrographolide, the best-characterised bioactive compound in AP, has been shown to have beneficial effects against atherosclerosis. However, there is little information about the effects and underlying mechanisms of the whole AP plant on the development of atherosclerosis. To address this question, we treated apolipoprotein E-deficient mice (on a cholesterol-enriched diet) with AP decoction via dietary supplementation. The biological mechanisms were studied in mouse primary peritoneal macrophages treated with crude serum preparations isolated from normal rats receiving vehicle or AP decoction treatment. We demonstrated that AP significantly reduced the plaque area in both thoracic and abdominal aortas in mice. In macrophage cells, genome-wide mRNA sequencing revealed that AP reversed ~ 70% of the genes responsive to lipopolysaccharides. Further bioinformatics analysis indicated that AP inhibited type I interferon (IFN) signalling. In mouse aortas and lipopolysaccharides-challenged macrophages, we confirmed that AP downregulated the expression of a panel of genes comprising the core modules in the type I IFN signalling. In particular, western blot experiments in macrophage cells demonstrated that AP significantly reduced the total protein level of signal transducer and activator of transcription 1 (STAT1), while IFN-β-induced STAT1 phosphorylation was not changed. In conclusion, given the established pathogenic effects of type I IFN in atherosclerosis, our results suggest that inhibition of the type I IFN signalling in macrophages is partly involved in the anti-atherogenic effects of Andrographis paniculata.

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“…We have reported one case of treatment-resistant seizures and the favorable effects of anakinra when used with a mTOR (mammalian target of rapamycin) blocker [58] . Recent results of randomized clinical trials of anakinra indicated attenuation of severe COVID-19 (coronavirus disease 2019) in hospitalized patients [59,60] , although a recent metanalysis reported negative results of anakinra for severe COVID-19 [61] . It is also of note that CAPS patients are expected to suffer from more potent adjuvant effects from vaccinations, but such effects are well attenuated with concurrent use of IL-1ß blockers [45] .…”

Section: Variants Of Genes Regulating Activation Of Inflammasomesmentioning

confidence: 99%

Inborn errors of immunity present with neuropsychiatric symptoms overlapping with autistic behavioral symptoms

Jyonouchi

2023

J Transl Genet Genom

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Autism spectrum disorder (ASD) is a behaviorally defined syndrome affected by multiple genetic and environmental factors. A wide variety of risk factors for ASD have been identified and many of these affect immune functions. This may not be surprising, since the immune system and the nervous system share common signaling mechanisms and affect each other as a part of the neuroimmune network. The ever-expanding scope of inborn errors of immunity (IEIs) has revealed multiple pathogenic gene variants that manifest overlapping clinical features of common neuropsychiatric diseases, including ASD. These IEIs often cause dysregulated immune activation and resultant chronic inflammation affecting multiple organs. Some IEIs also cause changes in morphogenesis and plasticity of the central nervous system. Such patients often present with a puzzling array of clinical features and some of them may be diagnosed with ASD or other neuropsychiatric conditions. The progress of our understanding of disease mechanisms for IEIs at the molecular levels has led to gene-specific treatment measures in some diseases. In addition, some ASD patients are found to have laboratory findings of neuroinflammation that resemble those seen in IEI patients. This may pave the way for applying specific treatment measures used for IEI patients in such ASD patients. This review focuses on describing IEIs that have overlapping features of ASD. Emphasis is also on IEIs that can be treated by targeting identified disease mechanisms. Such information may be helpful for clinicians who are considering genetic/metabolic workup in ASD patients.

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The regulatory landscape of macrophage interferon signaling in inflammation

Cited by 11 publications

References 182 publications

Interleukin 27, like interferons, activates JAK-STAT signaling and promotes pro-inflammatory and antiviral states that interfere with dengue and chikungunya viruses replication in human macrophages

Interleukin 27, like interferons, activates JAK-STAT signaling and promotes pro-inflammatory and antiviral states that interfere with dengue and chikungunya viruses replication in human macrophages

Inhibition of type I interferon signalling is involved in the anti-atherogenic effects of Andrographis paniculata

Inborn errors of immunity present with neuropsychiatric symptoms overlapping with autistic behavioral symptoms

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