Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses

Mayer‐Barber, Katrin D.; Yan, Bo

doi:10.1038/cmi.2016.25

Cited by 181 publications

(159 citation statements)

References 235 publications

(225 reference statements)

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“…Further, the discriminatory prowess of the signature against HIV was validated experimentally by qRT-PCR. HIV was chosen for comparison as it is well known that a common pathway dysregulated in both HIV and TB is the Type I interferon pathway (Mayer-Barber and Yan, 2016, Pawlowski et al, 2012). We show in this manuscript by validating the minimal marker in additional samples to those used for sequencing that the marker can distinguish TB subjects from healthy controls and HIV infected subjects, with reasonable accuracy.…”

Section: Discussionmentioning

confidence: 99%

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

et al. 2017

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Efficient diagnosis of tuberculosis (TB) is met with multiple challenges, calling for a shift of focus from pathogen-centric diagnostics towards identification of host-based multi-marker signatures. Transcriptomics offer a list of differentially expressed genes, but cannot by itself identify the most influential contributors to the disease phenotype. Here, we describe a computational pipeline that adopts an unbiased approach to identify a biomarker signature. Data from RNA sequencing from whole blood samples of TB patients were integrated with a curated genome-wide molecular interaction network, from which we obtain a comprehensive perspective of variations that occur in the host due to TB. We then implement a sensitive network mining method to shortlist gene candidates that are most central to the disease alterations. We then apply a series of filters that include applicability to multiple publicly available datasets as well as additional validation on independent patient samples, and identify a signature comprising 10 genes — FCGR1A, HK3, RAB13, RBBP8, IFI44L, TIMM10, BCL6, SMARCD3, CYP4F3 and SLPI, that can discriminate between TB and healthy controls as well as distinguish TB from latent tuberculosis and HIV in most cases. The signature has the potential to serve as a diagnostic marker of TB.

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Section: Discussionmentioning

confidence: 99%

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

et al. 2017

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“…Both IL-1 and type I IFN signaling pathways can cause harm when dysregulated or activated in an inappropriate context, and they also can regulate each other (50). IL-1 can antagonize type I IFN responses by regulating transcription and translation of IFN-␤ via induction of prostaglandin E 2 (57).…”

Section: Discussionmentioning

confidence: 99%

“…Type I IFNs are crucial regulators of noncanonical inflammasome activation and pyroptosis and can suppress IL-1␣ and IL-1␤ transcription and translation in various cell types (49). On the other hand, IL-1 can regulate type I IFN production and effector functions (50). We evaluated the mRNA levels of several genes related to innate immunity by using NanoString.…”

Section: Il-1 Signaling Modulates Mav-1 Replication and Bbb Permeabilmentioning

confidence: 99%

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

Castro-Jorge

Pretto

Smith

et al. 2017

J Virol

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Interleukin-1␤ (IL-1␤), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1 Ϫ/Ϫ mice). Il1r1 Ϫ/Ϫ mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1␤ production (Pycard Ϫ/Ϫ mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1 Ϫ/Ϫ mice). Pycard Ϫ/Ϫ and Unc93b1 Ϫ/Ϫ mice showed lower survival (similar to Il1r1 Ϫ/Ϫ mice) than control mice but, unlike Il1r1 Ϫ/Ϫ mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1 Ϫ/Ϫ mice had a very different inflammatory profile from infected Il1r1 Ϫ/Ϫ and Pycard Ϫ/Ϫ mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1 Ϫ/Ϫ mice. A time course of infection of control and Il1r1 Ϫ/Ϫ mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-␤ signaling may result in increased neuroinflammation. IMPORTANCEThe investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.

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“…Studies support a strong counter-regulation effect between IL-1 and type I IFN cytokine pathway, with elevated levels of IL-1b potently antagonizing type I IFN 22 . Thus, anakinra therapy may mitigate regulatory mechanisms on type I IFN leading to a paradoxical increase in granulomatous inflammation and a predominant Th1 cytokine response.…”

Section: Discussionmentioning

confidence: 97%

Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses

Cited by 181 publications

References 235 publications

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

Drug-induced sarcoidosis in a patient treated with an interleukin-1 receptor antagonist for hidradenitis suppurativa

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