Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors

Cell Rep. 2021 Nov 2;37(5):109955. doi: 10.1016/j.celrep.2021.109955.

Abstract

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.

Keywords: HDAC inhibitors; M1-type polarization; M2-type polarization; MEK signaling; age-related macular degeneration; kinase enrichment analysis; macrophage metabolism; macrophage polarization; phosphoproteomics; retinoic acid signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Energy Metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Interleukin-4 / pharmacology
  • Macrophage Activation / drug effects*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • Phenotype
  • Phosphorylation
  • Proof of Concept Study
  • Protein Kinase Inhibitors / pharmacology*
  • Proteome*
  • Proteomics*
  • Signal Transduction
  • THP-1 Cells
  • Time Factors
  • Tretinoin / pharmacology

Substances

  • Histone Deacetylase Inhibitors
  • PPAR gamma
  • Protein Kinase Inhibitors
  • Proteome
  • Interleukin-4
  • Tretinoin
  • Mitogen-Activated Protein Kinase Kinases