Cargando…

GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis

INTRODUCTION: Inhibition of STAT5 was recently reported to reduce murine atherosclerosis. However, the role of STAT5 isoforms, and more in particular STAT5A in macrophages in the context of human atherosclerosis remains unknown. METHODS AND RESULTS: Here, we demonstrate reciprocal expression regulat...

Descripción completa

Detalles Bibliográficos
Autores principales: Nagenborg, Jan, Jin, Han, Ruder, Adele V., Temmerman, Lieve, Mees, Barend, Schalkwijk, Casper, Müller-Klieser, Daniel, Berg, Thorsten, Goossens, Pieter, Donners, Marjo M. P. C., Biessen, Erik A. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619680/
https://www.ncbi.nlm.nih.gov/pubmed/37920458
http://dx.doi.org/10.3389/fimmu.2023.1165306
_version_ 1785130038997286912
author Nagenborg, Jan
Jin, Han
Ruder, Adele V.
Temmerman, Lieve
Mees, Barend
Schalkwijk, Casper
Müller-Klieser, Daniel
Berg, Thorsten
Goossens, Pieter
Donners, Marjo M. P. C.
Biessen, Erik A. L.
author_facet Nagenborg, Jan
Jin, Han
Ruder, Adele V.
Temmerman, Lieve
Mees, Barend
Schalkwijk, Casper
Müller-Klieser, Daniel
Berg, Thorsten
Goossens, Pieter
Donners, Marjo M. P. C.
Biessen, Erik A. L.
author_sort Nagenborg, Jan
collection PubMed
description INTRODUCTION: Inhibition of STAT5 was recently reported to reduce murine atherosclerosis. However, the role of STAT5 isoforms, and more in particular STAT5A in macrophages in the context of human atherosclerosis remains unknown. METHODS AND RESULTS: Here, we demonstrate reciprocal expression regulation of STAT5A and STAT5B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted the immune response, phagocytosis, cholesterol metabolism, and augmented apoptosis terms on transcriptional levels. These changes could partially be confirmed at functional level, with significant increases in apoptosis and decreases in lipid uptake and IL-6, IL-8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques. DISCUSSION: In summary, we identify STAT5A as an important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target in human atherosclerotic plaque inflammation.
format Online
Article
Text
id pubmed-10619680
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-106196802023-11-02 GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis Nagenborg, Jan Jin, Han Ruder, Adele V. Temmerman, Lieve Mees, Barend Schalkwijk, Casper Müller-Klieser, Daniel Berg, Thorsten Goossens, Pieter Donners, Marjo M. P. C. Biessen, Erik A. L. Front Immunol Immunology INTRODUCTION: Inhibition of STAT5 was recently reported to reduce murine atherosclerosis. However, the role of STAT5 isoforms, and more in particular STAT5A in macrophages in the context of human atherosclerosis remains unknown. METHODS AND RESULTS: Here, we demonstrate reciprocal expression regulation of STAT5A and STAT5B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted the immune response, phagocytosis, cholesterol metabolism, and augmented apoptosis terms on transcriptional levels. These changes could partially be confirmed at functional level, with significant increases in apoptosis and decreases in lipid uptake and IL-6, IL-8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques. DISCUSSION: In summary, we identify STAT5A as an important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target in human atherosclerotic plaque inflammation. Frontiers Media S.A. 2023-10-18 /pmc/articles/PMC10619680/ /pubmed/37920458 http://dx.doi.org/10.3389/fimmu.2023.1165306 Text en Copyright © 2023 Nagenborg, Jin, Ruder, Temmerman, Mees, Schalkwijk, Müller-Klieser, Berg, Goossens, Donners and Biessen https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Nagenborg, Jan
Jin, Han
Ruder, Adele V.
Temmerman, Lieve
Mees, Barend
Schalkwijk, Casper
Müller-Klieser, Daniel
Berg, Thorsten
Goossens, Pieter
Donners, Marjo M. P. C.
Biessen, Erik A. L.
GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title_full GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title_fullStr GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title_full_unstemmed GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title_short GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis
title_sort gm-csf-activated stat5a regulates macrophage functions and inflammation in atherosclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619680/
https://www.ncbi.nlm.nih.gov/pubmed/37920458
http://dx.doi.org/10.3389/fimmu.2023.1165306
work_keys_str_mv AT nagenborgjan gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT jinhan gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT ruderadelev gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT temmermanlieve gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT meesbarend gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT schalkwijkcasper gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT mullerklieserdaniel gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT bergthorsten gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT goossenspieter gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT donnersmarjompc gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis
AT biessenerikal gmcsfactivatedstat5aregulatesmacrophagefunctionsandinflammationinatherosclerosis