Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state

Laura A Bosmans; Claudia M van Tiel; Suzanne A B M Aarts; Lisa Willemsen; Jeroen Baardman; Bram W van Os; Myrthe den Toom; Linda Beckers; David J Ahern; Johannes H M Levels; Aldo Jongejan; Perry D Moerland; Sanne G S Verberk; Jan van den Bossche; Menno M P J de Winther; Christian Weber; Dorothee Atzler; Claudia Monaco; Norbert Gerdes; Annelie Shami; Esther Lutgens

doi:https://doi.org/10.1093/cvr/cvac084

Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state

Laura A Bosmans, Claudia M van Tiel, Suzanne A B M Aarts, Lisa Willemsen, Jeroen Baardman, Bram W van Os, Myrthe den Toom, Linda Beckers, David J Ahern, Johannes H M Levels, Aldo Jongejan, Perry D Moerland, Sanne G S Verberk, Jan van den Bossche, Menno M P J de Winther, Christian Weber, Dorothee Atzler, Claudia Monaco, Norbert Gerdes, Annelie ShamiEsther Lutgens

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signaling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-TNF Receptor Associated Factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.

METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, were reduced in CD40mac-/- compared to CD40wt mice and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses.Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206 + CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages (BMDMs) of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1 and Tns1).

CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

Original language	English
Journal	Cardiovascular Research
DOIs	https://doi.org/10.1093/cvr/cvac084
Publication status	E-pub ahead of print - 19 May 2022

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https://doi.org/10.1093/cvr/cvac084

Cite this

Bosmans, L. A., van Tiel, C. M., Aarts, S. A. B. M., Willemsen, L., Baardman, J., van Os, B. W., den Toom, M., Beckers, L., Ahern, D. J., Levels, J. H. M., Jongejan, A., Moerland, P. D., Verberk, S. G. S., van den Bossche, J., de Winther, M. M. P. J., Weber, C., Atzler, D., Monaco, C., Gerdes, N., ... Lutgens, E. (2022). Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state. Cardiovascular Research. https://doi.org/10.1093/cvr/cvac084

@article{3b33e29574ce47fba3e2107ce040bc6a,

title = "Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state",

abstract = "AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signaling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-TNF Receptor Associated Factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, were reduced in CD40mac-/- compared to CD40wt mice and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses.Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206 + CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages (BMDMs) of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1 and Tns1).CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.",

author = "Bosmans, {Laura A} and {van Tiel}, {Claudia M} and Aarts, {Suzanne A B M} and Lisa Willemsen and Jeroen Baardman and {van Os}, {Bram W} and {den Toom}, Myrthe and Linda Beckers and Ahern, {David J} and Levels, {Johannes H M} and Aldo Jongejan and Moerland, {Perry D} and Verberk, {Sanne G S} and {van den Bossche}, Jan and {de Winther}, {Menno M P J} and Christian Weber and Dorothee Atzler and Claudia Monaco and Norbert Gerdes and Annelie Shami and Esther Lutgens",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.",

year = "2022",

month = may,

day = "19",

doi = "https://doi.org/10.1093/cvr/cvac084",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

Bosmans, LA , van Tiel, CM, Aarts, SABM, Willemsen, L, Baardman, J, van Os, BW , den Toom, M , Beckers, L, Ahern, DJ, Levels, JHM , Jongejan, A , Moerland, PD, Verberk, SGS, van den Bossche, J , de Winther, MMPJ, Weber, C, Atzler, D, Monaco, C, Gerdes, N, Shami, A & Lutgens, E 2022, 'Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state', Cardiovascular Research. https://doi.org/10.1093/cvr/cvac084

TY - JOUR

T1 - Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state

AU - Bosmans, Laura A

AU - van Tiel, Claudia M

AU - Aarts, Suzanne A B M

AU - Willemsen, Lisa

AU - Baardman, Jeroen

AU - van Os, Bram W

AU - den Toom, Myrthe

AU - Beckers, Linda

AU - Ahern, David J

AU - Levels, Johannes H M

AU - Jongejan, Aldo

AU - Moerland, Perry D

AU - Verberk, Sanne G S

AU - van den Bossche, Jan

AU - de Winther, Menno M P J

AU - Weber, Christian

AU - Atzler, Dorothee

AU - Monaco, Claudia

AU - Gerdes, Norbert

AU - Shami, Annelie

AU - Lutgens, Esther

PY - 2022/5/19

Y1 - 2022/5/19

N2 - AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signaling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-TNF Receptor Associated Factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, were reduced in CD40mac-/- compared to CD40wt mice and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses.Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206 + CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages (BMDMs) of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1 and Tns1).CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

AB - AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signaling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-TNF Receptor Associated Factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice.METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, were reduced in CD40mac-/- compared to CD40wt mice and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses.Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206 + CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages (BMDMs) of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1 and Tns1).CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

U2 - https://doi.org/10.1093/cvr/cvac084

DO - https://doi.org/10.1093/cvr/cvac084

M3 - Article

C2 - 35587037

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

ER -