High-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming
Name
s41467-021-21066-x.pdf
Description
Published version
Size
8.27 MB
Format
Adobe PDF
Checksum (MD5)
3ef9710bee38d87f5c4803465787648a
Author(s)
Hu, Guangan
Su, Yang
Kang, Byong Ha
Fan, Zhongqi
Dong, Ting
Brown, Douglas R
Cheah, Jaime
Wittrup, Karl Dane
Chen, Jianzhu
Date Issued
2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41467-021-21066-x
