Pre-Existing Cytokine and NLRP3 Inflammasome Activation and Increased Vascular Permeability in Diabetes: A Possible Fatal Link With Worst COVID-19 Infection Outcomes?

Lambadiari, Vaia; Kousathana, Foteini; Raptis, Athanasios; Katogiannis, K; Kokkinos, Alexander; Ikonomidis, Ignatios

doi:10.3389/fimmu.2020.557235

Cited by 22 publications

(24 citation statements)

References 65 publications

(75 reference statements)

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“…In another review, patients with reduced immune fitness may exhibit inactivity of NLRP3 inflammasomes, leading to severe COVID-19 tissue damage and cytokine storm 22 . Furthermore, some researchers hypothesize that excessive activation of the NLRP3 inflammasome may be one of the main factors leading to serious complications in COVID-19 in patients with underlying uncontrolled diabetes 23 . A similar conclusion was reported in another review on obesity: the initial deficiency in defense mechanisms that was reflected in the increased susceptibility to SARS-CoV-2 in obesity-related metabolic disorders is most likely due to elevated systemic metabolic inflammation 24 , which is closely related to the NLRP3 inflammasome.…”

Section: Cholesterol Increases Susceptibility To Covid-19 By Causing Atherosclerosismentioning

confidence: 99%

Possible mechanisms of cholesterol elevation aggravating COVID-19

Tang¹,

Hu²,

Liu³

et al. 2021

Int. J. Med. Sci.

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Importance: Despite the availability of a vaccine against the severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with COVID-19 are recommended to continue lipid-lowering therapy.

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Section: Cholesterol Increases Susceptibility To Covid-19 By Causing Atherosclerosismentioning

confidence: 99%

Possible mechanisms of cholesterol elevation aggravating COVID-19

Tang¹,

Hu²,

Liu³

et al. 2021

Int. J. Med. Sci.

View full text Add to dashboard Cite

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“…The team hypothesised that diabetes-associated hyperactivation of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, chronic inflammation, hypercytokinemia, followed by increased vascular permeability might majorly contribute to the severity of Covid-19. The group also advised using colchicine, anti-IL1a, anti-IL1β, or anti-IL6 as a therapeutic intervention in overcoming the associated complications in Covid-19 ( Lambadiari et al, 2020 ). In another research by Korakas et al, explored the correlation between obesity and Covid-19.…”

Section: Delving Deeper Into the Pharmacodynamics Of Cq/hcq In Covid-mentioning

confidence: 99%

Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update

Joshi

Thakur

Mayank

et al. 2021

Food and Chemical Toxicology

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“…At the same time, SARS-CoV-2 activates the inflammasome through various mechanisms. More specifically, as SARS-CoV-2 enters the alveolar epithelial cells, it leads to their apoptosis, which, in turn, leads to the release of molecules that trigger NRP3 activation of the alveolar macrophages [ 83 ]. The virus also activates the inflammasome by binding ACE2 receptors on pneumonocytes, while its N proteins activate the complement cascade and release the C3a and C5a anaphylatoxins, which induce inflammasome activation as well [ 84 ].…”

Section: The Association Of T1dm With Sars-cov2 Infection: Pathophysiological Mechanismsmentioning

confidence: 99%

“…SARS-CoV-2 affects the vascular system directly by targeting endothelial cells through ACE2 receptor binding, leading to severe endothelial derangement and inflammation [ 120 , 121 , 122 ]. In addition, the overproduction of pro-inflammatory cytokines during COVID-19 promotes endothelial dysfunction [ 83 ]. Chen et al demonstrated that patients with severe COVID-19 disease displayed increased levels of pro-inflammatory cytokines, including soluble interleukin 2 receptor (IL-2R), IL-6, and TNF-a [ 7 ].…”

Section: The Association Of T1dm With Sars-cov2 Infection: Pathophysiological Mechanismsmentioning

confidence: 99%

Type 1 Diabetes Mellitus in the SARS-CoV-2 Pandemic: Oxidative Stress as a Major Pathophysiological Mechanism Linked to Adverse Clinical Outcomes

et al. 2021

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Recent reports have demonstrated the association between type 1 diabetes mellitus (T1DM) and increased morbidity and mortality rates during coronavirus disease (COVID-19) infection, setting a priority of these patients for vaccination. Impaired innate and adaptive immunity observed in T1DM seem to play a major role. Severe, life-threatening COVID-19 disease is characterized by the excessive release of pro-inflammatory cytokines, known as a “cytokine storm”. Patients with T1DM present elevated levels of cytokines including interleukin-1a (IL), IL-1β, IL-2, IL-6 and tumor necrosis factor alpha (TNF-α), suggesting the pre-existence of chronic inflammation, which, in turn, has been considered the major risk factor of adverse COVID-19 outcomes in many cohorts. Even more importantly, oxidative stress is a key player in COVID-19 pathogenesis and determines disease severity. It is well-known that extreme glucose excursions, the prominent feature of T1DM, are a potent mediator of oxidative stress through several pathways including the activation of protein kinase C (PKC) and the increased production of advanced glycation end products (AGEs). Additionally, chronic endothelial dysfunction and the hypercoagulant state observed in T1DM, in combination with the direct damage of endothelial cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may result in endothelial and microcirculation impairment, which contribute to the pathogenesis of acute respiratory syndrome and multi-organ failure. The binding of SARS-CoV-2 to angiotensin converting enzyme 2 (ACE2) receptors in pancreatic b-cells permits the direct destruction of b-cells, which contributes to the development of new-onset diabetes and the induction of diabetic ketoacidosis (DKA) in patients with T1DM. Large clinical studies are required to clarify the exact pathways through which T1DM results in worse COVID-19 outcomes.

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Pre-Existing Cytokine and NLRP3 Inflammasome Activation and Increased Vascular Permeability in Diabetes: A Possible Fatal Link With Worst COVID-19 Infection Outcomes?

Cited by 22 publications

References 65 publications

Possible mechanisms of cholesterol elevation aggravating COVID-19

Possible mechanisms of cholesterol elevation aggravating COVID-19

Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update

Type 1 Diabetes Mellitus in the SARS-CoV-2 Pandemic: Oxidative Stress as a Major Pathophysiological Mechanism Linked to Adverse Clinical Outcomes

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