TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis

BACKGROUND: Defective macrophage efferocytosis is a key driver of chronic nonresolving inflammation in dyslipidemia-associated diseases, such as obesity and atherosclerosis. However, the mechanism by which intracellular lipid accumulation impairs macrophage efferocytosis remains unclear. We hypothes...

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Autores: Singhal, Aarushi, Russo, Stefan, Dhawan, Umesh Kumar, Bhutia, Kunzangla, Bell, Christopher G., Hayat, Hedayatullah, Nightingale, Thomas D., de Gaetano, Monica, Belton, Orina, Brennan, Eoin, Munroe, Patricia B., Godson, Catherine, Barry, Mary, Shoulders, Carol C., Wilson, Heather L., Velasco Díez, Guillermo, Kiss-Toth, Endre, Subramanian, Manikandan
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/131935
Acceso en línea:https://hdl.handle.net/20.500.14352/131935
Access Level:acceso abierto
Palabra clave:616.15
616.1
612.1
616.12
Atherosclerosis
Efferocytosis
Endoplasmic reticulum
Macrophages
Hematología
Sistema cardiovascular
Cardiología
3205.04 Hematología
3207.04 Patología Cardiovascular
2411.03 Fisiología Cardiovascular
3205.01 Cardiología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/131935
network_acronym_str ES
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repository_id_str
spelling TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in AtherosclerosisSinghal, AarushiRusso, StefanDhawan, Umesh KumarBhutia, KunzanglaBell, Christopher G.Hayat, HedayatullahNightingale, Thomas D.de Gaetano, MonicaBelton, OrinaBrennan, EoinMunroe, Patricia B.Godson, CatherineBarry, MaryShoulders, Carol C.Wilson, Heather L.Velasco Díez, GuillermoKiss-Toth, EndreSubramanian, Manikandan616.15616.1612.1616.12AtherosclerosisEfferocytosisEndoplasmic reticulumMacrophagesHematologíaSistema cardiovascularCardiología3205.04 Hematología3207.04 Patología Cardiovascular2411.03 Fisiología Cardiovascular3205.01 CardiologíaBACKGROUND: Defective macrophage efferocytosis is a key driver of chronic nonresolving inflammation in dyslipidemia-associated diseases, such as obesity and atherosclerosis. However, the mechanism by which intracellular lipid accumulation impairs macrophage efferocytosis remains unclear. We hypothesized that lipid-induced endoplasmic reticulum (ER) stress mediates defective macrophage efferocytosis. METHODS: Bone marrow–derived macrophages were exposed to 7-ketocholesterol or palmitate to induce ER stress, and efferocytosis was quantified by measuring uptake of fluorescently labeled apoptotic cells with microscopy and flow cytometry. Key pathways were interrogated with pharmacological inhibitors, siRNA (silencing RNA), and in vivo models, including obese mice and in Ldlr−/− mice with hematopoietic-specific deletion of TRIB3 (Tribbles pseudokinase-3). Human relevance was assessed by testing efferocytosis in macrophages from individuals carrying the TRIB3 Q84R coronary artery disease risk variant (rs2295490) and by examining carotid endarterectomy samples. RESULTS: Activation of the ATF4 (activating transcription factor 4) branch of the ER stress pathway in lipid-loaded foamy macrophages led to upregulation of TRIB3, which triggered the downregulation of Rab27a, resulting in impaired focal exocytosis of intracellular membrane pools towards nascent, apoptotic cell–containing phagosomes. The resultant delay in phagosome closure stalled efferocytosis. In obese mice, this impairment was reversed using an ER stress–relieving chemical chaperone and via macrophage-specific knockdown of ATF4 or TRIB3. In atherosclerotic mice, hematopoietic cell–specific deletion of TRIB3 led to increased lesional efferocytosis, decreased plaque necrosis, and increased collagen, which are characteristic of stable plaques. In humans, TRIB3 expression was higher in vulnerable regions of carotid plaques, and macrophages from individuals carrying the gain-of-function TRIB3 Q84R risk variant expressed more TRIB3 and displayed decreased efferocytosis. CONCLUSIONS: Lipid-induced ER stress impairs macrophage efferocytosis via activation of the ATF4-TRIB3-Rab27a signaling axis, leading to exacerbated plaque necrosis. Targeted disruption of TRIB3 signaling in macrophages represents a novel therapeutic approach to promote efferocytosis and stabilize atherosclerotic plaques.American Heart AssociationUniversidad Complutense de Madrid20252025-12-0520252025-12-05journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/131935reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1319352026-06-02T12:44:21Z
dc.title.none.fl_str_mv TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
title TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
spellingShingle TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
Singhal, Aarushi
616.15
616.1
612.1
616.12
Atherosclerosis
Efferocytosis
Endoplasmic reticulum
Macrophages
Hematología
Sistema cardiovascular
Cardiología
3205.04 Hematología
3207.04 Patología Cardiovascular
2411.03 Fisiología Cardiovascular
3205.01 Cardiología
title_short TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
title_full TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
title_fullStr TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
title_full_unstemmed TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
title_sort TRIB3 Links Endoplasmic Reticulum Stress to Impaired Efferocytosis in Atherosclerosis
dc.creator.none.fl_str_mv Singhal, Aarushi
Russo, Stefan
Dhawan, Umesh Kumar
Bhutia, Kunzangla
Bell, Christopher G.
Hayat, Hedayatullah
Nightingale, Thomas D.
de Gaetano, Monica
Belton, Orina
Brennan, Eoin
Munroe, Patricia B.
Godson, Catherine
Barry, Mary
Shoulders, Carol C.
Wilson, Heather L.
Velasco Díez, Guillermo
Kiss-Toth, Endre
Subramanian, Manikandan
author Singhal, Aarushi
author_facet Singhal, Aarushi
Russo, Stefan
Dhawan, Umesh Kumar
Bhutia, Kunzangla
Bell, Christopher G.
Hayat, Hedayatullah
Nightingale, Thomas D.
de Gaetano, Monica
Belton, Orina
Brennan, Eoin
Munroe, Patricia B.
Godson, Catherine
Barry, Mary
Shoulders, Carol C.
Wilson, Heather L.
Velasco Díez, Guillermo
Kiss-Toth, Endre
Subramanian, Manikandan
author_role author
author2 Russo, Stefan
Dhawan, Umesh Kumar
Bhutia, Kunzangla
Bell, Christopher G.
Hayat, Hedayatullah
Nightingale, Thomas D.
de Gaetano, Monica
Belton, Orina
Brennan, Eoin
Munroe, Patricia B.
Godson, Catherine
Barry, Mary
Shoulders, Carol C.
Wilson, Heather L.
Velasco Díez, Guillermo
Kiss-Toth, Endre
Subramanian, Manikandan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.15
616.1
612.1
616.12
Atherosclerosis
Efferocytosis
Endoplasmic reticulum
Macrophages
Hematología
Sistema cardiovascular
Cardiología
3205.04 Hematología
3207.04 Patología Cardiovascular
2411.03 Fisiología Cardiovascular
3205.01 Cardiología
topic 616.15
616.1
612.1
616.12
Atherosclerosis
Efferocytosis
Endoplasmic reticulum
Macrophages
Hematología
Sistema cardiovascular
Cardiología
3205.04 Hematología
3207.04 Patología Cardiovascular
2411.03 Fisiología Cardiovascular
3205.01 Cardiología
description BACKGROUND: Defective macrophage efferocytosis is a key driver of chronic nonresolving inflammation in dyslipidemia-associated diseases, such as obesity and atherosclerosis. However, the mechanism by which intracellular lipid accumulation impairs macrophage efferocytosis remains unclear. We hypothesized that lipid-induced endoplasmic reticulum (ER) stress mediates defective macrophage efferocytosis. METHODS: Bone marrow–derived macrophages were exposed to 7-ketocholesterol or palmitate to induce ER stress, and efferocytosis was quantified by measuring uptake of fluorescently labeled apoptotic cells with microscopy and flow cytometry. Key pathways were interrogated with pharmacological inhibitors, siRNA (silencing RNA), and in vivo models, including obese mice and in Ldlr−/− mice with hematopoietic-specific deletion of TRIB3 (Tribbles pseudokinase-3). Human relevance was assessed by testing efferocytosis in macrophages from individuals carrying the TRIB3 Q84R coronary artery disease risk variant (rs2295490) and by examining carotid endarterectomy samples. RESULTS: Activation of the ATF4 (activating transcription factor 4) branch of the ER stress pathway in lipid-loaded foamy macrophages led to upregulation of TRIB3, which triggered the downregulation of Rab27a, resulting in impaired focal exocytosis of intracellular membrane pools towards nascent, apoptotic cell–containing phagosomes. The resultant delay in phagosome closure stalled efferocytosis. In obese mice, this impairment was reversed using an ER stress–relieving chemical chaperone and via macrophage-specific knockdown of ATF4 or TRIB3. In atherosclerotic mice, hematopoietic cell–specific deletion of TRIB3 led to increased lesional efferocytosis, decreased plaque necrosis, and increased collagen, which are characteristic of stable plaques. In humans, TRIB3 expression was higher in vulnerable regions of carotid plaques, and macrophages from individuals carrying the gain-of-function TRIB3 Q84R risk variant expressed more TRIB3 and displayed decreased efferocytosis. CONCLUSIONS: Lipid-induced ER stress impairs macrophage efferocytosis via activation of the ATF4-TRIB3-Rab27a signaling axis, leading to exacerbated plaque necrosis. Targeted disruption of TRIB3 signaling in macrophages represents a novel therapeutic approach to promote efferocytosis and stabilize atherosclerotic plaques.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-12-05
2025
2025-12-05
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/131935
url https://hdl.handle.net/20.500.14352/131935
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Heart Association
publisher.none.fl_str_mv American Heart Association
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415501590953984
score 15,81155

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