Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity

Immunity. 2019 Oct 15;51(4):655-670.e8. doi: 10.1016/j.immuni.2019.09.002. Epub 2019 Oct 3.


Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-β) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Cellular Microenvironment
  • Cellular Reprogramming
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kupffer Cells / physiology*
  • Liver / cytology
  • Liver / metabolism*
  • Liver X Receptors / genetics
  • Macrophages / physiology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / physiology*
  • Phenotype
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism


  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Intracellular Signaling Peptides and Proteins
  • Liver X Receptors
  • Membrane Proteins
  • Rbpj protein, mouse
  • Transforming Growth Factor beta
  • delta protein