Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche

• Published in: Immunity (Cambridge, Mass.) Mass.), 2019-10, Vol.51 (4), p.638-654.e9
• Main Authors: Bonnardel, Johnny, T’Jonck, Wouter, Gaublomme, Djoere, Browaeys, Robin, Scott, Charlotte L., Martens, Liesbet, Vanneste, Bavo, De Prijck, Sofie, Nedospasov, Sergei A., Kremer, Anna, Van Hamme, Evelien, Borghgraef, Peter, Toussaint, Wendy, De Bleser, Pieter, Mannaerts, Inge, Beschin, Alain, van Grunsven, Leo A., Lambrecht, Bart N., Taghon, Tom, Lippens, Saskia, Elewaut, Dirk, Saeys, Yvan, Guilliams, Martin
• Format: Article
• Language: English
• Subjects: Animals; Bmp9; Bone marrow; Cell activation; Cell adhesion molecules; Cell Communication; Cell cycle; Cell Differentiation; Cell interactions; Cells, Cultured; Cellular Microenvironment; Chemokines; Consortia; Deoxyribonucleic acid; Depletion; Developmental stages; DNA; endothelial cell; Endothelial cells; Endothelial Cells - physiology; Experiments; Female; fibroblast; Gene expression; Gene Expression Regulation; Hepatic Stellate Cells - physiology; Hepatocytes; Hepatocytes - physiology; Id3; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Interleukin 1; Kupffer cell; Kupffer cells; Kupffer Cells - physiology; Liver; Liver - cytology; Liver X receptors; Liver X Receptors - genetics; Liver X Receptors - metabolism; LXRa; macrophage; Macrophages; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; monocyte; Monocytes; Monocytes - physiology; niche; Notch; Nr1h3; Population; Receptors, Notch - metabolism; Recruitment; Statistical analysis; stellate cell; Stellate cells; Transcription factors; Tumor necrosis factor
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2019.08.017

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. [Display omitted] •Kupffer cells interact with stellate cells and hepatocytes in the space of Disse•TNF released by dying Kupffer cells activates stellate cells and endothelial cells•Stellate cells and endothelial cells orchestrate monocyte recruitment and adhesion•Endothelial and stellate cells induce LXR-α in monocytes via the NOTCH-BMP pathway Bonnardel and colleagues tracked monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting their identity. Monocytes transmigrated into the perisinusoidal space. Interactions with endothelial and stellate cells induced LXR-α via the NOTCH-BMP pathway. Hepatocytes induced ID3. Thus, stellate cells, hepatocytes, and endothelial cells compose the Kupffer cell niche.