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1.
Invest Ophthalmol Vis Sci ; 62(7): 25, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1280514

ABSTRACT

Purpose: The ocular surface is considered an important route for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. The expression level of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is vital for viral infection. However, the regulation of ACE2 expression on the ocular surface is still unknown. We aimed to determine the change in ACE2 expression in inflamed corneal epithelium and explore potential drugs to reduce the expression of ACE2 on the ocular surface. Methods: The expression of the SARS-CoV-2 receptors ACE2 and TMPRSS2 in human corneal epithelial cells (HCECs) was examined by qPCR and Western blotting. The altered expression of ACE2 in inflammatory corneal epithelium was evaluated in TNFα- and IL-1ß-stimulated HCECs and inflamed mouse corneal epithelium, and the effect of resveratrol on ACE2 expression in HCECs was detected by immunofluorescence and Western blot analysis. Results: ACE2 and TMPRSS2 are expressed on the human corneal epithelial cells. ACE2 expression is upregulated in HCECs by stimulation with TNFα and IL-1ß and inflamed mouse corneas, including dry eye and alkali-burned corneas. In addition, resveratrol attenuates the increased expression of ACE2 induced by TNFα in HCECs. Conclusions: This study demonstrates that ACE2 is highly expressed in HCECs and can be upregulated by stimulation with inflammatory cytokines and inflamed mouse corneal epithelium. Resveratrol may be able to reduce the increased expression of ACE2 on the inflammatory ocular surface. Our work suggests that patients with an inflammatory ocular surface may display higher ACE2 expression, which increases the risk of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Enzyme Inhibitors/pharmacology , Epithelium, Corneal/enzymology , Gene Expression Regulation, Enzymologic/physiology , Keratitis/enzymology , Resveratrol/pharmacology , SARS-CoV-2/physiology , Adult , Angiotensin-Converting Enzyme 2/metabolism , Animals , Blotting, Western , Cells, Cultured , Epithelium, Corneal/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Humans , Inflammation/drug therapy , Inflammation/enzymology , Interleukin-1beta/pharmacology , Keratitis/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microscopy, Fluorescence , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Virus/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation
2.
Sci Signal ; 14(673)2021 03 09.
Article in English | MEDLINE | ID: covidwho-1127536

ABSTRACT

IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.


Subject(s)
COVID-19/immunology , Interleukin-1beta/blood , T-Lymphocyte Subsets/immunology , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Flow Cytometry , Humans , Interleukin-1beta/pharmacology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Monocytes/classification , Monocytes/immunology , Monocytes/metabolism , NF-kappa B/blood , Pandemics , Phosphorylation , Receptors, CCR6/blood , SARS-CoV-2 , STAT Transcription Factors/blood , STAT Transcription Factors/immunology , Signal Transduction/immunology , T-Lymphocyte Subsets/metabolism , p38 Mitogen-Activated Protein Kinases/blood
3.
Int J Mol Sci ; 21(22)2020 Nov 10.
Article in English | MEDLINE | ID: covidwho-917002

ABSTRACT

Pro-inflammatory cytokines like interleukin-1ß (IL-1ß) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1ß on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1ß and used Atomic Force Microscopy to unveil that IL-1ß significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1ß stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1ß may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1ß-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1ß provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.


Subject(s)
Interleukin-1beta/physiology , Lung/physiology , Actins/metabolism , Adolescent , Adult , Biomechanical Phenomena , Cell Movement/drug effects , Cell Movement/physiology , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cells, Cultured , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type III/genetics , Collagen Type III/metabolism , Cyclooxygenase 2/metabolism , Elasticity/drug effects , Elasticity/physiology , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/physiology , Humans , Interleukin-1beta/pharmacology , Lung/cytology , Lung/drug effects , Male , Microscopy, Atomic Force , RNA, Messenger/genetics , RNA, Messenger/metabolism , Regeneration/genetics , Regeneration/physiology , Wound Healing/drug effects , Wound Healing/genetics , Wound Healing/physiology , Young Adult
4.
Mult Scler Relat Disord ; 46: 102540, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-803007

ABSTRACT

A long-term neurologic sequela arising from COVID-19 infection in multiple sclerosis (MS) patients could be related both to the increase of cytokines and the activation of NLRP3 inflammasome by the Sars-CoV2. These two mechanisms may cause a worsening of MS several months after the resolution of the infection.


Subject(s)
COVID-19/virology , Inflammasomes/metabolism , Multiple Sclerosis/complications , SARS-CoV-2/pathogenicity , COVID-19/complications , COVID-19/metabolism , Disease Progression , Humans , Interleukin-1beta/metabolism , Interleukin-1beta/pharmacology , Multiple Sclerosis/virology
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