Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation

By S. C. Huang, B. Everts, Yulia Ivanova, David O’Sullivan, Marcia Nascimento, A. Smith, W. Beatty, L. Love-Gregory, W. Lam, Christina M. O’Neill and 7 more. Nature Immunology, 2014

815 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/dd7687de2dc02c1fd36c6814f97c67f52a230afa

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In Epidemiology

1. Luke A. O'Neill
2. Klaus Ley
3. Edward J. Pearce

In Molecular Biology

1. Klaus Ley
2. Edward J. Pearce
3. Luke A. O'Neill

In Physiology

1. Edward J. Pearce
2. Alessandra Castegna
3. Luke A. O'Neill

Citations in the corpus

• The Metabolic Signature of Macrophage Responses (2019, background): “After that, all ingested lipids are processed by acid lipases within the lysosomes, leading to the generation of free fatty acids and cholesterol (147).”
• Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages (2019, background): “Ccl7 is known to be expressed by both M1 and M2 macrophages (78).”
• Immunometabolism governs dendritic cell and macrophage function (2016, background): “The oxidation of the fatty acids feeds the Krebs cycle and if lipolysis is inhibited, the M2 macrophage is less able to mediate resistance to parasitic helminth infection (Huang et al., 2014).”