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Nat Commun. 2016 Oct 12;7:13130. doi: 10.1038/ncomms13130.

Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals.

Author information

1
Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.
2
Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
3
The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
4
Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Osaka 565-0871, Japan.
5
Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
6
Department of Pathology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
7
DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Yamadaoka 3-1, Osaka 565-0871, Japan.
8
Global Application Development Center, Analytical and Measuring Instruments Division, Shimadzu Corporation, Kyoto 604-8511, Japan.

Abstract

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

PMID:
27731330
PMCID:
PMC5064021
DOI:
10.1038/ncomms13130
[Indexed for MEDLINE]
Free PMC Article

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