Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers

Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers

  • Metchnikov, E. Untersuchungen ueber die mesodermalen Phagocyten einiger Wirbeltiere. Biologisches Centralblatt 3, 560–565 (1883).


    Google Scholar
     

  • Browicz, T. Ueber intravasculäre Zellen in den Blutcapillaren der Leberacini. Arch. f. mikrosk. Anat. 55, 420–426 (1899).

    Article 

    Google Scholar
     

  • Sierro, F. et al. A liver capsular network of monocyte-derived macrophages restricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment. Immunity 47, 374–388.e6 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396.e38 (2022). This work integrated spatial transcriptomics and proteomics to map hepatic macrophage niches, showing that different subsets occupy evolutionarily conserved microenvironments that determine their identity and function.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Remmerie, A. et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, 641–657.e14 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tran, S. et al. Impaired Kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis. Immunity 53, 627–640.e5 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, J. & Kubes, P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165, 668–678 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Blériot, C. & Ginhoux, F. Understanding the heterogeneity of resident liver macrophages. Front. Immunol. 10, 2694 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015). This study overturned the dogma that tissue macrophages come from bone marrow, proving that yolk sac-derived erythro-myeloid progenitors give rise to a first wave of tissue macrophages during embryogenesis.

    Article 
    PubMed 

    Google Scholar
     

  • Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived. Cell 178, 1509–1525.e19 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016). This work provided functional evidence loss of embryonic KCs after liver injury opens the niche to circulating monocytes, which can engraft, self-renew and acquire the full identity of canonical KCs.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sakai, M. et al. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity 51, 655–670.e8 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bonnardel, J. et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654.e9 (2019). This work showed that KCs do not acquire their identity on their own but are instructed by signals from LSECs, hepatocytes and HSCs, highlighting the central role of this niche in shaping immune cell fate.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • David, B. A. et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151, 1176–1191 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Woltman, A. M., Boonstra, A., Naito, M. & Leenen, P. J. M. in Macrophages: Biology and Role in the Pathology of Diseases (eds Biswas, S. K. & Mantovani, A.) 217–247 (Springer, 2014).

  • Wong, C. H. Y., Jenne, C. N., Petri, B., Chrobok, N. L. & Kubes, P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat. Immunol. 14, 785–792 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blériot, C. et al. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42, 145–158 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Zeng, Z. et al. Sex-hormone-driven innate antibodies protect females and infants against EPEC infection. Nat. Immunol. 19, 1100–1111 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alemany, R., Suzuki, K. & Curiel, D. T. Blood clearance rates of adenovirus type 5 in mice. J. Gen. Virol. 81, 2605–2609 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deppermann, C. et al. Tacrolimus impairs Kupffer cell capacity to control bacteremia: why transplant recipients are susceptible to infection. Hepatology 73, 1967–1984 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sitia, G. et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog. 7, e1002061 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Furth, R. et al. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull. World Health Organ. 46, 845–852 (1972).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Deimann, W. & Fahimi, H. D. Peroxidase cytochemistry and ultrastructure of resident macrophages in fetal rat liver. Dev. Biol. 66, 43–56 (1978).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sorokin, S. P., Hoyt, R. F. & Grant, M. M. Development of macrophages in the lungs of fetal rabbits, rats, and hamsters. Anat. Rec. 208, 103–121 (1984).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bian, Z. et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Holt, P. G. & Jones, C. A. The development of the immune system during pregnancy and early life. Allergy 55, 688–697 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Popescu, D.-M. et al. Decoding human fetal liver haematopoiesis. Nature 574, 365–371 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Surewaard, B. G. J. & Kubes, P. Measurement of bacterial capture and phagosome maturation of Kupffer cells by intravital microscopy. Methods 128, 12–19 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McDonald, B. et al. Programing of an intravascular immune firewall by the gut microbiota protects against pathogen dissemination during infection. Cell Host Microbe 28, 660–668.e4 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hirako, I. C. et al. Uptake of Plasmodium chabaudi hemozoin drives Kupffer cell death and fuels superinfections. Sci. Rep. 12, 19805 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Araujo David, B. et al. Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis. Sci. Immunol. 9, eadq9704 (2024). This study challenged the dogma that KCs are sessile by showing that in neonates they can detach from the sinusoidal wall and migrate back into the lumen, where they intercept bacteria and protect against systemic infections.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bittmann, I. et al. The role of graft-resident Kupffer cells and lymphocytes of donor type during the time course after liver transplantation—a clinico-pathological study. Virchows Arch. 443, 541–548 (2003).

    Article 
    PubMed 

    Google Scholar
     

  • Pallett, L. J. et al. Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes. J. Exp. Med. 217, e20200050 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • MacParland, S. A. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andrews, T. S. et al. Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol. Commun. 6, 821–840 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seidman, J. S. et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 52, 1057–1074.e7 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klein, I. et al. Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110, 4077–4085 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beattie, L. et al. Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J. Hepatol. 65, 758–768 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guilliams, M. & Scott, C. L. Liver macrophages in health and disease. Immunity 55, 1515–1529 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, C.-Y. et al. CLEC4F is an inducible C-type lectin in F4/80-positive cells and is involved in alpha-galactosylceramide presentation in liver. PLoS ONE 8, e65070 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scott, C. L. et al. The transcription factor ZEB2 is required to maintain the tissue-specific identities of macrophages. Immunity 49, 312–325.e5 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, Y. et al. Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice. Cell Death Differ. 28, 3009–3021 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blériot, C. et al. A subset of Kupffer cells regulates metabolism through the expression of CD36. Immunity 54, 2101–2116.e6 (2021). This study identifies a new discrete Kupffer cell population that expands during metabolic challenges and displays distinct metabolic programs.

    Article 
    PubMed 

    Google Scholar
     

  • De Simone, G. et al. Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming. Immunity 54, 2089–2100.e8 (2021). This study showed that a Kupffer cell population can cross-present hepatocyte-derived antigens in response to IL-2, thereby sustaining the function of intrahepatic dysfunctional CD8⁺ T cells.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hume, D. A., Offermanns, S. & Bonnavion, R. Contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells. Immunity 55, 1139–1140 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Millard, S. M. et al. Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues. Cell Rep. 37, 110058 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • De Ponti, F. F. et al. Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair. Immunity 58, 362–380.e10 (2025). This work uncovered that both embryo-derived and monocyte-derived KCs can acquire a lipid-associated macrophage phenotype promoting tissue clearance and repair.

    Article 
    PubMed 

    Google Scholar
     

  • Xu, Y. et al. Identification of conserved and tissue-restricted transcriptional profiles for lipid associated macrophages. Commun. Biol. 8, 953 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900.e17 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dunsmore, G. et al. Timing and location dictate monocyte fate and their transition to tumor-associated macrophages. Sci. Immunol. 9, eadk3981 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698.e14 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, Y. et al. Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics. Dev. Cell 57, 398–414.e5 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miyamoto, Y. et al. Periportal macrophages protect against commensal-driven liver inflammation. Nature 629, 901–909 (2024). This study discovered a specialized population of periportal macrophages that sense gut-derived microbial signals and act as a frontline barrier preventing commensal-driven inflammation from spreading into the liver.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Martini, T., Naef, F. & Tchorz, J. S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu. Rev. Pathol. 18, 439–466 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ben-Moshe, S. et al. Spatial sorting enables comprehensive characterization of liver zonation. Nat. Metab. 1, 899–911 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobie, R. et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 29, 1832–1847.e8 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Inverso, D. et al. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver. Dev. Cell 56, 1677–1693.e10 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Iannacone, M. et al. Response to contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells. Immunity 55, 1141–1142 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sleyster, E. C. & Knook, D. L. Relation between localization and function of rat liver Kupffer cells. Lab. Invest. 47, 484–490 (1982).

    CAS 
    PubMed 

    Google Scholar
     

  • Bouwens, L., Baekeland, M., De Zanger, R. & Wisse, E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 6, 718–722 (1986).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bouwens, L., De Bleser, P., Vanderkerken, K., Geerts, B. & Wisse, E. Liver cell heterogeneity: functions of non-parenchymal cells. Enzyme 46, 155–168 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Itoh, Y. et al. Functional heterogeneity of rat liver macrophages: interleukin-1 secretion and Ia antigen expression in contrast with phagocytic activity. Liver 12, 26–33 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gola, A. et al. Commensal-driven immune zonation of the liver promotes host defence. Nature 589, 131–136 (2021). This work demonstrated that commensal-derived endotoxins activate LSECs to remodel the glycocalyx, enabling CXCL9 retention and positioning Kupffer cells around the portal tract through CXCR3-dependent recruitment.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Feng, D. et al. Characterisation of macrophages in healthy and diseased livers in mice: identification of necrotic lesion-associated macrophages. eGastroenterology 3, e100189 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ioannou, G. N. Epidemiology and risk-stratification of NAFLD-associated HCC. J. Hepatol. 75, 1476–1484 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Riazi, K. et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 7, 851–861 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alonso, C. et al. Metabolomic identification of subtypes of nonalcoholic steatohepatitis. Gastroenterology 152, 1449–1461.e7 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335–1347 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Diniz, A. B. et al. Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD. JHEP Rep. 2, 100117 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Govaere, O. et al. Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease. J. Hepatol. 76, 1001–1012 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, H. et al. Kupffer cell programming by maternal obesity triggers fatty liver disease. Nature 644, 790–798 (2025). This study showed that maternal obesity epigenetically reprograms fetal KCs towards glycolytic metabolism, creating a long-lasting imprint that promotes lipid accumulation and fatty liver disease in offspring.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e5 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo, W. et al. Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease. Immunity 57, 2310–2327.e6 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Daemen, S. et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 34, 108626 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Krenkel, O. et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 69, 551–563 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morinaga, H. et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64, 1120–1130 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morgantini, C. et al. Liver macrophages regulate systemic metabolism through non-inflammatory factors. Nat. Metab. 1, 445–459 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kohyama, M. et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Haldar, M. et al. Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156, 1223–1234 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Willy, P. J. et al. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 9, 1033–1045 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spann, N. J. & Glass, C. K. Sterols and oxysterols in immune cell function. Nat. Immunol. 14, 893–900 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Calkin, A. C. & Tontonoz, P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol. 13, 213–224 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spann, N. J. et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151, 138–152 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pehkonen, P. et al. Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages. BMC Genomics 13, 50 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Costet, P., Luo, Y., Wang, N. & Tall, A. R. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275, 28240–28245 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Venkateswaran, A. et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα. Proc. Natl Acad. Sci. USA 97, 12097–12102 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Westerterp, M. et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ. Res. 112, 1456–1465 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wan, J. et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130–142 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Francque, S. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat. Rev. Gastroenterol. Hepatol. 18, 24–39 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, S. C.-C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pfeffer, S. R. NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes. J. Biol. Chem. 294, 1706–1709 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kanamori, Y. et al. Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH. iScience 24, 102032 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Theurl, I. et al. On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat. Med. 22, 945–951 (2016). This work showed that, during acute haemolysis, monocyte-derived macrophages transiently colonize the liver to clear damaged erythrocytes and recycle iron, revealing a flexible backup system that complements the homeostatic role of KCs.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Willekens, F. L. A. et al. Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105, 2141–2145 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, S.-J., Park, S.-Y., Jung, M.-Y., Bae, S. M. & Kim, I.-S. Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver. Blood 117, 5215–5223 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Park, M. D., Silvin, A., Ginhoux, F. & Merad, M. Macrophages in health and disease. Cell 185, 4259–4279 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175.e14 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hegde, S. et al. Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours. Nature 646, 1214–1222 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • English, K. et al. A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs. Nat. Commun. 15, 1261 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Iannacone, M. & Guidotti, L. G. Immunobiology and pathogenesis of hepatitis B virus infection. Nat. Rev. Immunol. 22, 19–32 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Venzin, V. et al. CD4 + T cells license Kupffer cells to reverse CD8 + T cell dysfunction induced by hepatocellular priming. Nat. Immunol. https://doi.org/10.1038/s41590-025-02199-3 (2025). This study demonstrated that CD4⁺ T cells directly interact with KCs in the liver through CD40–CD40L, inducing IL-12 and IL-27 production, with IL-27 being essential to sustain antiviral CD8⁺ T cell function.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, H. et al. Hepatitis B virus particles preferably induce Kupffer cells to produce TGF-β1 over pro-inflammatory cytokines. Dig. Liver Dis. 44, 328–333 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tian, Y. et al. Kupffer cell-dependent TNF-alpha signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse. Proc. Natl Acad. Sci. USA 103, 4598–4603 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ait Ahmed, Y. et al. Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners. Cell. Mol. Immunol. 18, 2165–2176 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tian, Y., Kuo, C.-F., Akbari, O. & Ou, J.-H. J. Maternal-derived hepatitis b virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission. Immunity 44, 1204–1214 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, W.-Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat. Immunol. 11, 295–302 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liew, P. X., Lee, W.-Y. & Kubes, P. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 47, 752–765.e5 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Van Der Meijden, P. E. J. & Heemskerk, J. W. M. Platelet biology and functions: new concepts and clinical perspectives. Nat. Rev. Cardiol. 16, 166–179 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Deppermann, C. et al. Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets. J. Exp. Med. 217, e20190723 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Helmy, K. Y. et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915–927 (2006). This seminal work identified CRIg as a KC-specific receptor and a dominant component of the phagocytic system mediating rapid clearance of C3-opsonized particles from the circulation.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Holers, V. M. Complement and its receptors: new insights into human disease. Annu. Rev. Immunol. 32, 433–459 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • He, J. Q. et al. CRIg mediates early Kupffer cell responses to adenovirus. J. Leukoc. Biol. 93, 301–306 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, Z. et al. CRIg functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne Gram-positive bacteria. Cell Host Microbe 20, 99–106 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Canton, J., Neculai, D. & Grinstein, S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 13, 621–634 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Surewaard, B. G. J. et al. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J. Exp. Med. 213, 1141–1151 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Surewaard, B. G. J. et al. α-Toxin induces platelet aggregation and liver injury during Staphylococcus aureus sepsis. Cell Host Microbe 24, 271–284.e3 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jorch, S. K. et al. Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination. J. Clin. Invest. 129, 4643–4656 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hommes, J. W. & Surewaard, B. G. J. Intracellular habitation of Staphylococcus aureus: molecular mechanisms and prospects for antimicrobial therapy. Biomedicines 10, 1804 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Egen, J. G. et al. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28, 271–284 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • An, H. et al. Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria. J. Exp. Med. 219, e20212032 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, X. et al. Capsule type defines the capability of Klebsiella pneumoniae in evading Kupffer cell capture in the liver. PLoS Pathog. 18, e1010693 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • An, H. et al. Splenic red pulp macrophages eliminate the liver-resistant Streptococcus pneumoniae from the blood circulation of mice. Sci. Adv. 11, eadq6399 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Deniset, J. F., Surewaard, B. G., Lee, W.-Y. & Kubes, P. Splenic Ly6Ghigh mature and Ly6Gint immature neutrophils contribute to eradication of S. pneumoniae. J. Exp. Med. 214, 1333–1350 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, J. et al. Liver macrophages and sinusoidal endothelial cells execute vaccine-elicited capture of invasive bacteria. Sci. Transl. Med. 15, eade0054 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tian, X. et al. Natural antibodies to polysaccharide capsules enable Kupffer cells to capture invading bacteria in the liver sinusoids. J. Exp. Med. 222, e20240735 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lopes, M. E. et al. Susceptibility to infections during acute liver injury depends on transient disruption of liver macrophage niche. Front. Immunol. 13, 892114 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Triantafyllou, E. et al. PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury. J. Clin. Invest. 131, e140196 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peiseler, M. et al. Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver. Science 381, eabq5202 (2023). This work discovered that, in liver fibrosis, monocyte-derived macrophages can fuse into multinucleated syncytia that occupy the Kupffer cell niche and partially restore its filtering functions.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Borst, K. et al. Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J. Hepatol. 68, 682–690 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, W. et al. In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis. J. Clin. Invest. 133, e157937 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brown, G. D. et al. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv13 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Sun, D. et al. Fungal dissemination is limited by liver macrophage filtration of the blood. Nat. Commun. 10, 4566 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, Y.-Y., Shiau, S. & Fang, C.-T. Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. PLoS ONE 10, e0119090 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Singh, N. et al. Cryptococcosis in patients with cirrhosis of the liver and posttransplant outcomes. Transplantation 99, 2132–2141 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Spec, A., Raval, K. & Powderly, W. G. End-stage liver disease is a strong predictor of early mortality in cryptococcosis. Open. Forum Infect. Dis. 3, ofv197 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Beattie, L. et al. Dynamic imaging of experimental Leishmania donovani-induced hepatic granulomas detects Kupffer cell-restricted antigen presentation to antigen-specific CD8 T cells. PLoS Pathog. 6, e1000805 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moyo, D. et al. Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling. Front. Immunol. 9, 637 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pessenda, G. et al. Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis. Nat. Commun. 16, 3125 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Musrati, M. A. et al. Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells. J. Hepatol. 81, 1023–1039 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kourtzelis, I., Hajishengallis, G. & Chavakis, T. Phagocytosis of apoptotic cells in resolution of inflammation. Front. Immunol. 11, 553 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doran, A. C., Yurdagul, A. & Tabas, I. Efferocytosis in health and disease. Nat. Rev. Immunol. 20, 254–267 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liebold, I. et al. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages. Science 384, eabo7027 (2024). This study revealed that macrophages interpret IL-4 signals differently depending on the type of apoptotic cell they engulf, showing that efferocytosis imprints a context-specific transcriptional and functional state that shapes tissue repair and immune regulation.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Horst, A. K., Tiegs, G. & Diehl, L. Contribution of macrophage efferocytosis to liver homeostasis and disease. Front. Immunol. 10, 2670 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sitia, G., Iannacone, M., Müller, S., Bianchi, M. E. & Guidotti, L. G. Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice. J. Leukoc. Biol. 81, 100–107 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dong, S. et al. Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. J. Toxicol. Sci. 41, 561–572 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miyazaki, H. et al. Fatty acid binding protein 7 regulates phagocytosis and cytokine production in Kupffer cells during liver injury. Am. J. Pathol. 184, 2505–2515 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shi, H. et al. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis. Sci. Transl. Med. 17, eadv2106 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rumgay, H. et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J. Hepatol. 77, 1598–1606 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horn, S. R. et al. Epidemiology of liver metastases. Cancer Epidemiol. 67, 101760 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Sharma, A. et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 183, 377–394.e21 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sharma, A., Blériot, C., Currenti, J. & Ginhoux, F. Oncofetal reprogramming in tumour development and progression. Nat. Rev. Cancer 22, 593–602 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kimura, Y. et al. The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc. Natl Acad. Sci. USA 113, 14097–14102 (2016). This work showed that KCs protect the liver at the onset of metastatic dissemination by using Dectin-2 to phagocytose circulating cancer cells, in contrast to their immunosuppressive role once the tumour is established.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gül, N. et al. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J. Clin. Invest. 124, 812–823 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Deng, Z. et al. The nuclear factor ID3 endows macrophages with a potent anti-tumour activity. Nature 626, 864–873 (2024). This study showed that ID3 programs a Kupffer cell transcriptional state that enhances phagocytosis of metastatic cells and recruitment of cytotoxic lymphocytes, uncovering a core mechanism by which KCs suppress liver tumour growth.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, P. et al. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat. Commun. 13, 5782 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, G. et al. Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature 618, 374–382 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wortzel, I. et al. Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression. Nat. Cancer 5, 1815–1833 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352–356 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Halpern, K. B. et al. Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells. Nat. Biotechnol. 36, 962–970 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hildebrandt, F. et al. Spatial transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver. Nat. Commun. 12, 7046 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blériot, C., Dunsmore, G., Alonso-Curbelo, D. & Ginhoux, F. A temporal perspective for tumor-associated macrophage identities and functions. Cancer Cell https://doi.org/10.1016/j.ccell.2024.04.002 (2024).

  • Michels, D. A., Parker, M. & Salas-Solano, O. Quantitative impurity analysis of monoclonal antibody size heterogeneity by CE-LIF: example of development and validation through a quality-by-design framework. Electrophoresis 33, 815–826 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Breitkopf-Heinlein, K. et al. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut 66, 939–954 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhao, D. et al. ALK1 signaling is required for the homeostasis of Kupffer cells and prevention of bacterial infection. J. Clin. Invest. 132, e150489 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Ganguly, S. et al. Lipid-associated macrophages’ promotion of fibrosis resolution during MASH regression requires TREM2. Proc. Natl Acad. Sci. USA 121, e2405746121 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar