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Sci Rep. 2017 Aug 25;7(1):9417. doi: 10.1038/s41598-017-09639-7.

A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ.

Author information

1
Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Yong In, 17104, Republic of Korea. jieunlim8575@gmail.com.
2
Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Yong In, 17104, Republic of Korea. chungek@hanmail.net.
3
Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Yong In, 17104, Republic of Korea. ysson@khu.ac.kr.
4
Kyung Hee Institute of Regenerative Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea. ysson@khu.ac.kr.

Abstract

Macrophage polarization plays an important role in tissue damage and repair. In this study, we show that Substance-P (SP) can directly induce M2 polarization of inflammatory macrophages. SP induced the differentiation of GM-CSF-differentiated pro-inflammatory macrophages into alternatively activated phagocytic M2 like macrophages (M2SP) through direct activation of the PI3K/Akt/mTOR/S6kinase pathway and induction of Arginase-1, CD163, and CD206, all of which were nullified by pretreatment with the neurokinin-1 receptor (NK-1R) antagonist RP67580 and specific signaling pathway inhibitors. M2SP were distinct from IL-4/IL-13-induced M2a and IL-10-induced M2c subtypes; they did not show STAT activation and exhibited high phagocytic and endothelial adhesive activity. Furthermore, SP had a dominant effect on M2 polarization over Interferon gamma (IFNγ), a potent M1-skewing cytokine, and effectively induced the M2 phenotype in monocytes and the human THP-1 cell line. Finally, adoptively transferred M2SP migrated to a spinal cord injury (SCI) lesion site and improved functional recovery. Collectively, our findings show that SP, a neuropeptide, plays a role as a novel cytokine by inducing tissue-repairing M2SP macrophages and thus may be developed for pharmacological intervention in diseases involving chronic inflammation and acute injury.

PMID:
28842601
PMCID:
PMC5573373
DOI:
10.1038/s41598-017-09639-7
[Indexed for MEDLINE]
Free PMC Article

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