Stellate cells, hepatocytes and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche (microarray)

Macrophages are strongly adapted to their tissue of residence. Yet, we know little 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 the 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 ID3 and LXRα. Coordinated interactions with hepatocytes induced ID3 expression, while endothelial cells and stellate cells induced LXRα 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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Bonnardel J, T'Jonck W, Gaublomme D, Browaeys R, Scott CL, Martens L, Vanneste B, De Prijck S, Nedospasov SA, Kremer A, Van Hamme E, Borghgraef P, Toussaint W, De Bleser P, Mannaerts I, Beschin A, van Grunsven LA, Lambrecht BN, Taghon T, Lippens S, Elewaut D, Saeys Y, Guilliams M