Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages

Stanley Ching Cheng Huang; Bart Everts; Yulia Ivanova; David O'Sullivan; Marcia Nascimento; Amber M. Smith; Wandy Beatty; Latisha Love-Gregory; Wing Y. Lam; Christina M. O'Neill; Cong Yan; Hong Du; Nada A. Abumrad; Joseph F. Urban; Maxim N. Artyomov; Erika L. Pearce; Edward J. Pearce

doi:10.1038/ni.2956

Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages

Stanley Ching Cheng Huang, Bart Everts, Yulia Ivanova, David O'Sullivan, Marcia Nascimento, Amber M. Smith, Wandy Beatty, Latisha Love-Gregory, Wing Y. Lam, Christina M. O'Neill, Cong Yan, Hong Du, Nada A. Abumrad, Joseph F. Urban, Maxim N. Artyomov, Erika L. Pearce, Edward J. Pearce

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867 Scopus citations

Abstract

Alternative (M2) activation of macrophages driven via the α -chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

Original language	English
Pages (from-to)	846-855
Number of pages	10
Journal	Nature immunology
Volume	15
Issue number	9
DOIs	https://doi.org/10.1038/ni.2956
State	Published - Sep 2014

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Huang, S. C. C., Everts, B., Ivanova, Y., O'Sullivan, D., Nascimento, M., Smith, A. M., Beatty, W., Love-Gregory, L., Lam, W. Y., O'Neill, C. M., Yan, C., Du, H., Abumrad, N. A., Urban, J. F., Artyomov, M. N., Pearce, E. L., & Pearce, E. J. (2014). Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nature immunology, 15(9), 846-855. https://doi.org/10.1038/ni.2956

@article{e86344cc3bb04a198fd25beda7950dc1,

title = "Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages",

abstract = "Alternative (M2) activation of macrophages driven via the α -chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.",

author = "Huang, {Stanley Ching Cheng} and Bart Everts and Yulia Ivanova and David O'Sullivan and Marcia Nascimento and Smith, {Amber M.} and Wandy Beatty and Latisha Love-Gregory and Lam, {Wing Y.} and O'Neill, {Christina M.} and Cong Yan and Hong Du and Abumrad, {Nada A.} and Urban, {Joseph F.} and Artyomov, {Maxim N.} and Pearce, {Erika L.} and Pearce, {Edward J.}",

note = "Funding Information: We thank G. Haemmerle and R. Zechner for permission to use Pnpla2−/− mice; C. Semenkovich (Washington University in St. Louis) and R. Gross (Washington University in St. Louis) for Pnpla2−/− mice; H. Virgin, E.L. Gautier and S. Ivanov for discussions; and the staff of the Department of Pathology & Immunology Flow Cytometry Core and the Metabolomics Core of the Diabetic Cardiovascular Disease Center for technical assistance. Supported by the US National Institutes of Health (AI32573 and CA164062 to E.J.P.; AI091965 and CA158823 to E.L.P.; DK060022 to N.A.A.; HL087001 to H.D.; and CA138759 and CA152099 to C.Y.).",

year = "2014",

month = sep,

doi = "10.1038/ni.2956",

language = "English",

volume = "15",

pages = "846--855",

journal = "Nature immunology",

issn = "1529-2908",

number = "9",

}

Huang, SCC, Everts, B, Ivanova, Y, O'Sullivan, D, Nascimento, M, Smith, AM, Beatty, W, Love-Gregory, L, Lam, WY, O'Neill, CM, Yan, C, Du, H, Abumrad, NA, Urban, JF, Artyomov, MN, Pearce, EL & Pearce, EJ 2014, 'Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages', Nature immunology, vol. 15, no. 9, pp. 846-855. https://doi.org/10.1038/ni.2956

TY - JOUR

T1 - Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages

AU - Huang, Stanley Ching Cheng

AU - Everts, Bart

AU - Ivanova, Yulia

AU - O'Sullivan, David

AU - Nascimento, Marcia

AU - Smith, Amber M.

AU - Beatty, Wandy

AU - Love-Gregory, Latisha

AU - Lam, Wing Y.

AU - O'Neill, Christina M.

AU - Yan, Cong

AU - Du, Hong

AU - Abumrad, Nada A.

AU - Urban, Joseph F.

AU - Artyomov, Maxim N.

AU - Pearce, Erika L.

AU - Pearce, Edward J.

N1 - Funding Information: We thank G. Haemmerle and R. Zechner for permission to use Pnpla2−/− mice; C. Semenkovich (Washington University in St. Louis) and R. Gross (Washington University in St. Louis) for Pnpla2−/− mice; H. Virgin, E.L. Gautier and S. Ivanov for discussions; and the staff of the Department of Pathology & Immunology Flow Cytometry Core and the Metabolomics Core of the Diabetic Cardiovascular Disease Center for technical assistance. Supported by the US National Institutes of Health (AI32573 and CA164062 to E.J.P.; AI091965 and CA158823 to E.L.P.; DK060022 to N.A.A.; HL087001 to H.D.; and CA138759 and CA152099 to C.Y.).

PY - 2014/9

Y1 - 2014/9

N2 - Alternative (M2) activation of macrophages driven via the α -chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

AB - Alternative (M2) activation of macrophages driven via the α -chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

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U2 - 10.1038/ni.2956

DO - 10.1038/ni.2956

M3 - Article

C2 - 25086775

AN - SCOPUS:84906319549

SN - 1529-2908

VL - 15

SP - 846

EP - 855

JO - Nature immunology

JF - Nature immunology

IS - 9

ER -

Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages

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