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Macrophage Liver Imprinted by Stellate Cells

Johnny Bonnardel, Wouter T’Jonck, Djoere Gaublomme, Robin Browaeys, Charlotte L. Scott, Liesbet Martens, Bavo Vanneste, Sofie De Prijck, Sergei A. Nedospasov, Anna Kremer, Evelien Van Hamme, Peter Borghgraef, Wendy Toussaint, Pieter De Bleser,
Inge Mannaerts, Alain Beschin, Leo A. van Grunsven, Bart N. Lambrecht, Tom Taghon, Saskia Lippens, Dirk Elewaut, Yvan Saeys, Martin Guilliams



Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches.

Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity.

Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment.

Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α).

Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway.

This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.


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