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.

Echinacea purpurea-derived homogeneous polysaccharide exerts anti-tumor efficacy via facilitating M1 macrophage polarization

“…M1 macrophages are characterized by secreting a large amount of mediators, including IL-1β and TNF-α. 21 , 22 EPPA significantly enhanced the secretion of IL-1β ( Figure 4 A), while reducing the TNF-α concentration in M1 macrophages ( Figure 4 B).

Figure 4 EPPA suppresses M1 macrophage inflammation (A and B) The secretion of IL-1β (A) and TNF-α (B) from M1 macrophages treated with or without EPPA (500 μg/mL) (n = 3).

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Whole-genome sequencing of extrachromosomal circular DNA of cerebrospinal fluid of medulloblastoma

“…Furthermore, TBCK (TBC1 domain containing kinase) may be involved in the transcriptional regulation of components of the mammalian target of the rapamycin (mTOR) complex and has also been associated with neuronal developmental disorders ( 84 , 85 ). Finally, IFNGR2 (interferon-gamma receptor 2) encodes a protein that is the non-ligand binding β-chain of the gamma interferon receptor, and its possible involvement in interleukin (IL)-1β-dependent inflammation was noted in recent studies ( 86 , 87 ).…”

Circadian orchestration of host and gut microbiota in infection

“…Furthermore, many infectious diseases involve circadian disruptions, and thus are related to the disruption of melatonin secretion, indicating that restoration of circadian rhythms by melatonin administration might exert therapeutic benefits. Indeed, the potential of melatonin against bacterial infections via both direct and/or indirect mechanisms has been well recognized and is documented elsewhere (Pereira & Garcia, 2021; Xie et al ., 2020; Xia et al ., 2019, 2022; He et al ., 2021, 2022; Liu et al ., 2020). Melatonin could be a useful weapon against different viral infections in animals or humans, including against coronaviruses (Crespo et al ., 2016; Huang et al ., 2010; Zhou et al ., 2020; Zhai et al ., 2021), functioning as an adjuvant for combating infectious diseases in a time‐of‐day‐dependent manner.…”

“…Furthermore, many infectious diseases involve circadian disruptions, and thus are related to the disruption of melatonin secretion, indicating that restoration of circadian rhythms by melatonin administration might exert therapeutic benefits. Indeed, the potential of melatonin against bacterial infections via both direct and/or indirect mechanisms has been well recognized and is documented elsewhere (Pereira & Garcia, 2021;Xie et al, 2020;Xia et al, 2019Xia et al, , 2022He et al, 2021He et al, , 2022Liu et al, 2020) Circadian rhythms in infection Zhai et al, 2021), functioning as an adjuvant for combating infectious diseases in a time-of-day-dependent manner. Moreover, the gut microbiota has both local intestinal and/or systemic effects (chiefly in the liver) in metabolizing drugs, altering their therapeutic efficacy due to circadian rhythm-directed hepatic drug metabolism (S. Lin et al, 2019).…”