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.

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Acknowledgements

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.).

Author information

Author notes

    • Bart Everts
    • , Yulia Ivanova
    •  & David O'Sullivan

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Stanley Ching-Cheng Huang
    • , Bart Everts
    • , Yulia Ivanova
    • , David O'Sullivan
    • , Marcia Nascimento
    • , Amber M Smith
    • , Wing Y Lam
    • , Christina M O'Neill
    • , Maxim N Artyomov
    • , Erika L Pearce
    •  & Edward J Pearce
  2. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Wandy Beatty
  3. Department of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Latisha Love-Gregory
    •  & Nada A Abumrad
  4. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indiana, USA.

    • Cong Yan
    •  & Hong Du
  5. US Department of Agriculture, Agriculture Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, Maryland, USA.

    • Joseph F Urban Jr

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Contributions

S.C.-C.H., B.E., Y.I., D.O., M.N., N.A.A., J.F.U., M.N.A., E.L.P. and E.J.P., designed experiments; S.C.-C.H., B.E., Y.I., D.O., M.N., A.M.S., W.B., L.L.-G., W.Y.L., C.M.O., C.Y. and H.D. did experiments; S.C.-C.H., B.E., M.N., D.O., W.Y.L., C.M.O., N.A.A., M.N.A., E.L.P. and E.J.P. analyzed data; and S.C.-C.H. and E.J.P. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Edward J Pearce.

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https://doi.org/10.1038/ni.2956

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