Choline uptake is vital for IL-1β-driven inflammation

Leake, Isobel

doi:10.1038/s41584-019-0228-4

Cited by 5 publications

(6 citation statements)

References 1 publication

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“…IL-1β is an essential proinflammatory cytokine acting as a fever-inducing pyrogen in the host (Kugelberg, 2016; Leake, 2019). In vivo , the NLRP3 inflammasome is required for IL-1β processing, with caspase -1 and ASC oligomerization mediating IL-1β maturation and secretion.…”

Section: Discussionmentioning

confidence: 99%

Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

et al. 2019

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Dengue virus (DENV) infection causes several diseases ranging from dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome characterized by endothelial dysfunction, vascular leakage, and shock. Here, we identify a potential mechanism by which DENV induces tissue injury and vascular leakage by promoting the activation of interleukin (IL)-1β. DENV facilitates IL-1β secretion in infected patients, mice, human peripheral blood mononuclear cells (PBMCs), mouse bone marrow-derived macrophages (BMDMs), and monocyte-differentiated macrophages (THP-1) via activating the NLRP3 inflammasome. The accumulated data suggest that IL-1β probably induces vascular leakage and tissue injury in interferon-alpha/beta receptor 1 deficient C57BL/6 mice (IFNAR–/– C57BL/6), whereas IL-1 receptor antagonist (IL-1RA) alleviates these effects of IL-1β. Finally, administration of recombinant IL-1β protein results in vascular leakage and tissue injury in C57BL/6 mice. Together, the accumulated results demonstrate that IL-1β contributes to DENV-associated pathology and suggest that IL-1RA acts as a potential agent for the treatment of DENV-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

et al. 2019

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“…Previous studies have shown that exposure to LPS induces choline uptake by macrophages to activate the NLRP3 inflammasome while blocking choline uptake prevents NLRP3 inflammasome assembly 37–39 . We tested if one of the mechanisms of Miltefosine anti-inflammasome activity is via reduced choline uptake.…”

Section: Resultsmentioning

confidence: 99%

“…Miltefosine blunts endotoxin-induced choline uptake. Previous studies have shown that exposure to LPS induces choline uptake by macrophages to activate the NLRP3 inflammasome while blocking choline uptake prevents NLRP3 inflammasome assembly [37][38][39] .…”

mentioning

confidence: 99%

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Traughber

Iacano

Khan

et al. 2022

Preprint

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Excess cholesterol induces foam cell formation, NLRP3 inflammasome activation, and IL-1β release in atherosclerotic plaques. We have shown previously that Miltefosine increased cholesterol release and dampened NLRP3 inflammasome assembly in macrophages. Here, we show that Miltefosine reduced LPS-induced choline uptake by macrophages and attenuated NLRP3 inflammasome assembly in mice. Miltefosine-fed mice showed reduced plasma IL-1β in a polymicrobial cecal slurry injection model of systemic inflammation. Miltefosine-fed mice showed increased reverse cholesterol transport from macrophages to plasma, liver, and feces. Hyperlipidemic apoE-/- mice fed with Miltefosine showed significantly reduced weight gain and markedly reduced atherosclerotic lesions vs. control mice. 16S rDNA sequencing and analysis showed alterations in the gut microbiota profile of Miltefosine-fed hyperlipidemic apoE-/- vs. control mice, with the most notable changes in Romboutsia and Bacteroidetes species. Taken together, these data indicate that Miltefosine causes pleiotropic effects on lipid metabolism, inflammasome activity, atherosclerosis, and the gut microbiota.

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“…Of note, vesicular ACh transporters (VAChTs) are involved in the storage of ACh. Alterations of VAChTs are linked with the release of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and interleukin 6 (IL-6) (Leake 2019 ). The exact functions of VAChTs in the immune cells were not elucidated.…”

Section: Cholinergic System and Inflammationmentioning

confidence: 99%

“…The exact functions of VAChTs in the immune cells were not elucidated. The experimental study demonstrated that choline uptake is necessary for macrophage activation and IL-1β-mediated inflammation (Leake 2019 ; Hernandez et al 2013 ).…”

Section: Cholinergic System and Inflammationmentioning

confidence: 99%

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best

Nadwa

Al-Kuraishy

Al-Gareeb

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

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Choline uptake is vital for IL-1β-driven inflammation

Cited by 5 publications

References 1 publication

Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

Dengue Virus Infection Activates Interleukin-1β to Induce Tissue Injury and Vascular Leakage

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best

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