Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Ada Weinstock; Karishma Rahman; Or Yaacov; Hitoo Nishi; Prashanthi Menon; Cyrus A. Nikain; Michela L. Garabedian; Stephanie Pena; Naveed Akbar; Brian E. Sansbury; Sean P. Heffron; Jianhua Liu; Gregory Marecki; Dawn Fernandez; Emily J. Brown; Kelly V. Ruggles; Stephen A. Ramsey; Chiara Giannarelli; Matthew Spite; Robin P. Choudhury; P’Ng Loke; Edward A. Fisher

doi:10.7554/eLife.67932

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Ada Weinstock, Karishma Rahman, Or Yaacov, Hitoo Nishi, Prashanthi Menon, Cyrus A. Nikain, Michela L. Garabedian, Stephanie Pena, Naveed Akbar, Brian E. Sansbury, Sean P. Heffron, Jianhua Liu, Gregory Marecki, Dawn Fernandez, Emily J. Brown, Kelly V. Ruggles, Stephen A. Ramsey, Chiara Giannarelli, Matthew Spite, Robin P. ChoudhuryP’Ng Loke, Edward A. Fisher

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Abstract

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4^-/-Il13^-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE₂/STAT3 axis.

Original language	English
Article number	e67932
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.67932
State	Published - Mar 2021

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10.7554/eLife.67932

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Weinstock, A., Rahman, K., Yaacov, O., Nishi, H., Menon, P., Nikain, C. A., Garabedian, M. L., Pena, S., Akbar, N., Sansbury, B. E., Heffron, S. P., Liu, J., Marecki, G., Fernandez, D., Brown, E. J., Ruggles, K. V., Ramsey, S. A., Giannarelli, C., Spite, M., ... Fisher, E. A. (2021). Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis. eLife, 10, [e67932]. https://doi.org/10.7554/eLife.67932

@article{e818ea999d2e44eaafafd68b834d6714,

title = "Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis",

abstract = "Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.",

author = "Ada Weinstock and Karishma Rahman and Or Yaacov and Hitoo Nishi and Prashanthi Menon and Nikain, {Cyrus A.} and Garabedian, {Michela L.} and Stephanie Pena and Naveed Akbar and Sansbury, {Brian E.} and Heffron, {Sean P.} and Jianhua Liu and Gregory Marecki and Dawn Fernandez and Brown, {Emily J.} and Ruggles, {Kelly V.} and Ramsey, {Stephen A.} and Chiara Giannarelli and Matthew Spite and Choudhury, {Robin P.} and P{\textquoteright}Ng Loke and Fisher, {Edward A.}",

note = "Funding Information: We thank Drs. Thomas Wynn and Richard Locksley for providing mice used in this study. We also thank Mark Graham and Richard Lee (Ionis Pharmaceuticals) for graciously providing the ApoB ASO. SPH is supported by the NIH (K23HL135398). CG is supported by the American Heart Association (AHA, 20SFRN35210252) and the NIH (R03HL13528, K23HL111339, R21TR001739, UH2/ 3TR002067). DF is supported by NIH training grant 5T23HL007824. MS acknowledges the support of NIH grants HL106173 and GM095467. BES was supported by a National Research Service Award from the NIH (HL136044). This research was supported in part by the Intramural Research Program of the NIH to PL, as well as NIH grants AI130945, AI133977, HL084312, and U.S. Department of Defense (DoD) award W81XWH-16-1-0256. EAF acknowledges support from NIH grants HL084312 and DoD award W81XWH-16-1-0256. AW was supported by the AHA (18POST34080390) and the NIH (K99HL151963). KR was supported by NIH training grants T32GM007308 and T32AI100853, and NIH fellowship F30HL131183. Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved.",

year = "2021",

month = mar,

doi = "10.7554/eLife.67932",

language = "English",

volume = "10",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

Weinstock, A, Rahman, K, Yaacov, O, Nishi, H, Menon, P, Nikain, CA, Garabedian, ML, Pena, S, Akbar, N, Sansbury, BE, Heffron, SP, Liu, J, Marecki, G, Fernandez, D, Brown, EJ, Ruggles, KV, Ramsey, SA, Giannarelli, C, Spite, M, Choudhury, RP, Loke, PN & Fisher, EA 2021, 'Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis', eLife, vol. 10, e67932. https://doi.org/10.7554/eLife.67932

TY - JOUR

T1 - Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

AU - Weinstock, Ada

AU - Rahman, Karishma

AU - Yaacov, Or

AU - Nishi, Hitoo

AU - Menon, Prashanthi

AU - Nikain, Cyrus A.

AU - Garabedian, Michela L.

AU - Pena, Stephanie

AU - Akbar, Naveed

AU - Sansbury, Brian E.

AU - Heffron, Sean P.

AU - Liu, Jianhua

AU - Marecki, Gregory

AU - Fernandez, Dawn

AU - Brown, Emily J.

AU - Ruggles, Kelly V.

AU - Ramsey, Stephen A.

AU - Giannarelli, Chiara

AU - Spite, Matthew

AU - Choudhury, Robin P.

AU - Loke, P’Ng

AU - Fisher, Edward A.

N1 - Funding Information: We thank Drs. Thomas Wynn and Richard Locksley for providing mice used in this study. We also thank Mark Graham and Richard Lee (Ionis Pharmaceuticals) for graciously providing the ApoB ASO. SPH is supported by the NIH (K23HL135398). CG is supported by the American Heart Association (AHA, 20SFRN35210252) and the NIH (R03HL13528, K23HL111339, R21TR001739, UH2/ 3TR002067). DF is supported by NIH training grant 5T23HL007824. MS acknowledges the support of NIH grants HL106173 and GM095467. BES was supported by a National Research Service Award from the NIH (HL136044). This research was supported in part by the Intramural Research Program of the NIH to PL, as well as NIH grants AI130945, AI133977, HL084312, and U.S. Department of Defense (DoD) award W81XWH-16-1-0256. EAF acknowledges support from NIH grants HL084312 and DoD award W81XWH-16-1-0256. AW was supported by the AHA (18POST34080390) and the NIH (K99HL151963). KR was supported by NIH training grants T32GM007308 and T32AI100853, and NIH fellowship F30HL131183. Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.

AB - Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.

UR - http://www.scopus.com/inward/record.url?scp=85103337842&partnerID=8YFLogxK

U2 - 10.7554/eLife.67932

DO - 10.7554/eLife.67932

M3 - Article

C2 - 33720008

AN - SCOPUS:85103337842

VL - 10

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e67932

ER -

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

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