Cargando…

Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis

Interleukin-33 (IL-33) acts as an ‘alarmin’, and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT)...

Descripción completa

Detalles Bibliográficos
Autores principales: Tembhre, Manoj Kumar, Sriwastva, Mukesh Kumar, Hote, Milind Padmakar, Srivastava, Shikha, Solanki, Priyanka, Imran, Shafaque, Lakshmy, Ramakrishnan, Sharma, Alpana, Jaiswal, Kailash, Upadhyay, Ashish Datt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774908/
https://www.ncbi.nlm.nih.gov/pubmed/36552551
http://dx.doi.org/10.3390/antiox11122343
_version_ 1784855514393346048
author Tembhre, Manoj Kumar
Sriwastva, Mukesh Kumar
Hote, Milind Padmakar
Srivastava, Shikha
Solanki, Priyanka
Imran, Shafaque
Lakshmy, Ramakrishnan
Sharma, Alpana
Jaiswal, Kailash
Upadhyay, Ashish Datt
author_facet Tembhre, Manoj Kumar
Sriwastva, Mukesh Kumar
Hote, Milind Padmakar
Srivastava, Shikha
Solanki, Priyanka
Imran, Shafaque
Lakshmy, Ramakrishnan
Sharma, Alpana
Jaiswal, Kailash
Upadhyay, Ashish Datt
author_sort Tembhre, Manoj Kumar
collection PubMed
description Interleukin-33 (IL-33) acts as an ‘alarmin’, and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT.
format Online
Article
Text
id pubmed-9774908
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97749082022-12-23 Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis Tembhre, Manoj Kumar Sriwastva, Mukesh Kumar Hote, Milind Padmakar Srivastava, Shikha Solanki, Priyanka Imran, Shafaque Lakshmy, Ramakrishnan Sharma, Alpana Jaiswal, Kailash Upadhyay, Ashish Datt Antioxidants (Basel) Article Interleukin-33 (IL-33) acts as an ‘alarmin’, and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT. MDPI 2022-11-26 /pmc/articles/PMC9774908/ /pubmed/36552551 http://dx.doi.org/10.3390/antiox11122343 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tembhre, Manoj Kumar
Sriwastva, Mukesh Kumar
Hote, Milind Padmakar
Srivastava, Shikha
Solanki, Priyanka
Imran, Shafaque
Lakshmy, Ramakrishnan
Sharma, Alpana
Jaiswal, Kailash
Upadhyay, Ashish Datt
Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title_full Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title_fullStr Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title_full_unstemmed Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title_short Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis
title_sort interleukin-33 induces neutrophil extracellular trap (net) formation and macrophage necroptosis via enhancing oxidative stress and secretion of proatherogenic factors in advanced atherosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774908/
https://www.ncbi.nlm.nih.gov/pubmed/36552551
http://dx.doi.org/10.3390/antiox11122343
work_keys_str_mv AT tembhremanojkumar interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT sriwastvamukeshkumar interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT hotemilindpadmakar interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT srivastavashikha interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT solankipriyanka interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT imranshafaque interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT lakshmyramakrishnan interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT sharmaalpana interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT jaiswalkailash interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis
AT upadhyayashishdatt interleukin33inducesneutrophilextracellulartrapnetformationandmacrophagenecroptosisviaenhancingoxidativestressandsecretionofproatherogenicfactorsinadvancedatherosclerosis