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

Tetsuya Kimura (), Shigeyuki Nada, Noriko Takegahara, Tatsusada Okuno, Satoshi Nojima, Sujin Kang, Daisuke Ito, Keiko Morimoto, Takashi Hosokawa, Yoshitomo Hayama, Yuichi Mitsui, Natsuki Sakurai, Hana Sarashina-Kida, Masayuki Nishide, Yohei Maeda, Hyota Takamatsu, Daisuke Okuzaki, Masaki Yamada, Masato Okada and Atsushi Kumanogoh ()
Additional contact information
Tetsuya Kimura: World Premier International Immunology Frontier Research Center, Osaka University
Shigeyuki Nada: Research Institute for Microbial Diseases, Osaka University
Noriko Takegahara: World Premier International Immunology Frontier Research Center, Osaka University
Tatsusada Okuno: World Premier International Immunology Frontier Research Center, Osaka University
Satoshi Nojima: World Premier International Immunology Frontier Research Center, Osaka University
Sujin Kang: World Premier International Immunology Frontier Research Center, Osaka University
Daisuke Ito: World Premier International Immunology Frontier Research Center, Osaka University
Keiko Morimoto: World Premier International Immunology Frontier Research Center, Osaka University
Takashi Hosokawa: World Premier International Immunology Frontier Research Center, Osaka University
Yoshitomo Hayama: World Premier International Immunology Frontier Research Center, Osaka University
Yuichi Mitsui: World Premier International Immunology Frontier Research Center, Osaka University
Natsuki Sakurai: World Premier International Immunology Frontier Research Center, Osaka University
Hana Sarashina-Kida: World Premier International Immunology Frontier Research Center, Osaka University
Masayuki Nishide: World Premier International Immunology Frontier Research Center, Osaka University
Yohei Maeda: World Premier International Immunology Frontier Research Center, Osaka University
Hyota Takamatsu: World Premier International Immunology Frontier Research Center, Osaka University
Daisuke Okuzaki: DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases
Masaki Yamada: Global Application Development Center, Shimadzu Corporation
Masato Okada: Research Institute for Microbial Diseases, Osaka University
Atsushi Kumanogoh: World Premier International Immunology Frontier Research Center, Osaka University

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13130

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