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Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

Mulholland, Megan LU ; Depuydt, Marie A C LU ; Jakobsson, Gabriel LU ; Ljungcrantz, Irena LU ; Grentzmann, Andrietta LU ; To, Fong LU ; Bengtsson, Eva LU orcid ; Jaensson Gyllenbäck, Elin LU ; Grönberg, Caitríona LU and Rattik, Sara LU , et al. (2024) In Cardiovascular Research
Abstract

AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis.

METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice... (More)

AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis.

METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade.

CONCLUSION: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.

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organization
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type
Contribution to journal
publication status
epub
subject
in
Cardiovascular Research
publisher
Oxford University Press
external identifiers
  • pmid:38563353
ISSN
1755-3245
DOI
10.1093/cvr/cvae046
language
English
LU publication?
yes
additional info
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
id
80fa6bd9-20ea-4637-a74c-4096c786e389
date added to LUP
2024-04-08 15:25:45
date last changed
2024-04-08 15:50:55
@article{80fa6bd9-20ea-4637-a74c-4096c786e389,
  abstract     = {{<p>AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis.</p><p>METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade.</p><p>CONCLUSION: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.</p>}},
  author       = {{Mulholland, Megan and Depuydt, Marie A C and Jakobsson, Gabriel and Ljungcrantz, Irena and Grentzmann, Andrietta and To, Fong and Bengtsson, Eva and Jaensson Gyllenbäck, Elin and Grönberg, Caitríona and Rattik, Sara and Liberg, David and Schiopu, Alexandru and Björkbacka, Harry and Kuiper, Johan and Bot, Ilze and Slütter, Bram and Engelbertsen, Daniel}},
  issn         = {{1755-3245}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Oxford University Press}},
  series       = {{Cardiovascular Research}},
  title        = {{Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation}},
  url          = {{http://dx.doi.org/10.1093/cvr/cvae046}},
  doi          = {{10.1093/cvr/cvae046}},
  year         = {{2024}},
}