IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation

Nat Immunol. 2022 Feb;23(2):217-228. doi: 10.1038/s41590-021-01117-7. Epub 2022 Jan 31.

Abstract

During inflammation, Ly6Chi monocytes are rapidly mobilized from the bone marrow (BM) and are recruited into inflamed tissues, where they undergo monocyte-to-phagocyte transition (MTPT). The in vivo developmental trajectories of the MTPT and the contribution of individual cytokines to this process remain unclear. Here, we used a murine model of neuroinflammation to investigate how granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), two type 1 cytokines, controlled MTPT. Using genetic fate mapping, gene targeting and high-dimensional single-cell multiomics analyses, we found that IFNγ was essential for the gradual acquisition of a mature inflammatory phagocyte phenotype in Ly6Chi monocytes, while GM-CSF was required to license interleukin-1β (IL-1β) production, phagocytosis and oxidative burst. These results suggest that the proinflammatory cytokine environment guided MTPT trajectories in the inflamed central nervous system (CNS) and indicated that GM-CSF was the most prominent target for the disarming of monocyte progenies during neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cytokines / metabolism
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Interferon-gamma / metabolism*
  • Macrophages / metabolism
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Monocytes / metabolism*
  • Monocytes / physiology
  • Neuroinflammatory Diseases / metabolism*
  • Neuroinflammatory Diseases / physiopathology
  • Phagocytes / metabolism*
  • Phagocytes / physiology

Substances

  • Cytokines
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor