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; Atsushi Kumanogoh

doi:10.1038/ncomms13130

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, Atsushi Kumanogoh

Research output: Contribution to journal › Article › peer-review

85 Citations (Scopus)

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.

Original language	English
Article number	13130
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13130
Publication status	Published - 2016 Oct 12
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms13130

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Kimura, T., Nada, S., Takegahara, N., Okuno, T., Nojima, S., Kang, S., Ito, D., Morimoto, K., Hosokawa, T., Hayama, Y., Mitsui, Y., Sakurai, N., Sarashina-Kida, H., Nishide, M., Maeda, Y., Takamatsu, H., Okuzaki, D., Yamada, M., Okada, M., & Kumanogoh, A. (2016). Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals. Nature communications, 7, [13130]. https://doi.org/10.1038/ncomms13130

Kimura, T, Nada, S, Takegahara, N, Okuno, T, Nojima, S, Kang, S, Ito, D, Morimoto, K, Hosokawa, T, Hayama, Y, Mitsui, Y, Sakurai, N, Sarashina-Kida, H, Nishide, M, Maeda, Y, Takamatsu, H, Okuzaki, D, Yamada, M, Okada, M & Kumanogoh, A 2016, 'Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals', Nature communications, vol. 7, 13130. https://doi.org/10.1038/ncomms13130

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title = "Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals",

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.",

author = "Tetsuya Kimura and Shigeyuki Nada and Noriko Takegahara and Tatsusada Okuno and Satoshi Nojima and Sujin Kang and Daisuke Ito and Keiko Morimoto and Takashi Hosokawa and Yoshitomo Hayama and Yuichi Mitsui and Natsuki Sakurai and Hana Sarashina-Kida and Masayuki Nishide and Yohei Maeda and Hyota Takamatsu and Daisuke Okuzaki and Masaki Yamada and Masato Okada and Atsushi Kumanogoh",

note = "Funding Information: We thank Prof. Shizuo Akira (WPI Immunology Frontier Research Center, Osaka, Japan) for providing LysM-Cre mice. This work was supported by the following grants: research grants and Center of Innovation program (COI-STREAM) grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan; a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan (#14525051 to A. Kumanogoh); an AMED-CREST grant from the Japan Agency for Medical Research and Development (#15652237 to A. Kumanogoh); Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED (#15653290 to A. Kumanogoh); Japan Society for the Promotion of Science (JSPS) KAKENHI Grants (#26650120 to S. Nada; # 25117716, #15H04296 and #26640078 to M. Okada); and a Grant-in-Aid for JSPS Fellows (#23-56423 to T. Kimura). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

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doi = "10.1038/ncomms13130",

language = "English",

volume = "7",

journal = "Nature Communications",

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T1 - Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals

AU - Kimura, Tetsuya

AU - Nada, Shigeyuki

AU - Takegahara, Noriko

AU - Okuno, Tatsusada

AU - Nojima, Satoshi

AU - Kang, Sujin

AU - Ito, Daisuke

AU - Morimoto, Keiko

AU - Hosokawa, Takashi

AU - Hayama, Yoshitomo

AU - Mitsui, Yuichi

AU - Sakurai, Natsuki

AU - Sarashina-Kida, Hana

AU - Nishide, Masayuki

AU - Maeda, Yohei

AU - Takamatsu, Hyota

AU - Okuzaki, Daisuke

AU - Yamada, Masaki

AU - Okada, Masato

AU - Kumanogoh, Atsushi

N1 - Funding Information: We thank Prof. Shizuo Akira (WPI Immunology Frontier Research Center, Osaka, Japan) for providing LysM-Cre mice. This work was supported by the following grants: research grants and Center of Innovation program (COI-STREAM) grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan; a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan (#14525051 to A. Kumanogoh); an AMED-CREST grant from the Japan Agency for Medical Research and Development (#15652237 to A. Kumanogoh); Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED (#15653290 to A. Kumanogoh); Japan Society for the Promotion of Science (JSPS) KAKENHI Grants (#26650120 to S. Nada; # 25117716, #15H04296 and #26640078 to M. Okada); and a Grant-in-Aid for JSPS Fellows (#23-56423 to T. Kimura). Publisher Copyright: © The Author(s) 2016.

PY - 2016/10/12

Y1 - 2016/10/12

N2 - 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.

AB - 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.

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

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