Dataset Information

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.

ABSTRACT:

Background

Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined.

Methods

Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)-infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA-seq, metabolomics, and genetic manipulation) were conducted to reveal the mechanism whereby melatonergic signalling reduces macrophage inflammation.

Results

Here, we demonstrate that melatonergic activation substantially lessens interleukin (IL)-1β-dependent inflammation. Treatment of macrophages with melatonin rewires metabolic program, as well as remodels signalling pathways which depends on interferon regulatory factor (IRF) 7. Mechanistically, melatonin acts via membrane receptor (MT) 1 to increase heat shock factor (Hsf) 1 expression through lowering the inactive glycogen synthase kinase (GSK3) β, thereby transcriptionally inhibiting interferon (IFN)-γ receptor (IFNGR) 2 and ultimately causing defective canonical signalling events [Janus kinase (JAK) 1/2-signal transducer and activator of transcription (STAT) 1-IRF7] and lower IL-1β production in macrophages. Moreover, we find that melatonin amplifies host protective responses to PmCQ2 infection-induced pneumonia.

Conclusions

Our conceptual framework provides potential therapeutic targets to prevent and/or treat inflammatory diseases associating with excessive IL-1β production.

SUBMITTER: Xia Y

PROVIDER: S-EPMC8858632 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.

Xia Yaoyao Y Zhang Qingzhuo Q Ye Yuyi Y Wu Xiaoyan X He Fang F Peng Yuanyi Y Yin Yulong Y Ren Wenkai W

Clinical and translational medicine 20220201 2

<h4>Background</h4>Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined.<h4>Methods</h4>Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)-infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA-seq, metabo ...[more]

PMID: 35184395

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Project description:BackgroundInflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear.ObjectiveTo determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.DesignExploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846).SettingMany clinical sites in 39 countries.Participants8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry.InterventionRandom assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.MeasurementsPrimary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women).ResultsAnemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher.LimitationCANTOS was not designed to assess the cause of anemia in individual trial participants.ConclusionThese exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia.Primary funding sourceNovartis Pharmaceuticals.

Dataset Information

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.

Background

Methods

Results

Conclusions

Publications

Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.

Similar Datasets

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