Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors
Lizhi He,
Jhih-Hua Jhong,
Qi Chen,
Kai-Yao Huang,
Karin Strittmatter,
Johannes Kreuzer,
Michael DeRan,
Xu Wu,
Tzong-Yi Lee,
Nikolai Slavov,
Wilhelm Haas,
Alexander G. Marneros
Affiliations
Lizhi He
Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA
Jhih-Hua Jhong
Department of Computer Science and Engineering, Yuan Ze University, Taoyuan 320, Taiwan; Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China
Qi Chen
Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China
Kai-Yao Huang
Department of Medical Research, Hsinchu Mackay Memorial Hospital, Hsinchu 300, Taiwan
Karin Strittmatter
Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA
Johannes Kreuzer
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Michael DeRan
Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA
Xu Wu
Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA
Tzong-Yi Lee
Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China
Nikolai Slavov
Department of Bioengineering and Department of Biology, Northeastern University, Boston, MA 02115, USA
Wilhelm Haas
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Alexander G. Marneros
Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA; Corresponding author
Summary: Macrophages undergoing M1- versus M2-type polarization differ significantly in their cell metabolism and cellular functions. Here, global quantitative time-course proteomics and phosphoproteomics paired with transcriptomics provide a comprehensive characterization of temporal changes in cell metabolism, cellular functions, and signaling pathways that occur during the induction phase of M1- versus M2-type polarization. Significant differences in, especially, metabolic pathways are observed, including changes in glucose metabolism, glycosaminoglycan metabolism, and retinoic acid signaling. Kinase-enrichment analysis shows activation patterns of specific kinases that are distinct in M1- versus M2-type polarization. M2-type polarization inhibitor drug screens identify drugs that selectively block M2- but not M1-type polarization, including mitogen-activated protein kinase kinase (MEK) and histone deacetylase (HDAC) inhibitors. These datasets provide a comprehensive resource to identify specific signaling and metabolic pathways that are critical for macrophage polarization. In a proof-of-principle approach, we use these datasets to show that MEK signaling is required for M2-type polarization by promoting peroxisome proliferator-activated receptor-γ (PPARγ)-induced retinoic acid signaling.
