Epigenetic Regulation of Kupffer Cell Function in Health and Disease

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Feb 12

PMID 33574817

Citations 22

Authors

Hunter Bennett

Ty D Troutman

Mashito Sakai

Christopher K Glass

Affiliations

Soon will be listed here.

Abstract

Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

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References

Rong X, Albert C, Hong C, Duerr M, Chamberlain B, Tarling E . LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab. 2013; 18(5):685-97. PMC: 3889491. DOI: 10.1016/j.cmet.2013.10.002. View

Franklin R, Liao W, Sarkar A, Kim M, Bivona M, Liu K . The cellular and molecular origin of tumor-associated macrophages. Science. 2014; 344(6186):921-5. PMC: 4204732. DOI: 10.1126/science.1252510. View

Bonnardel J, TJonck W, Gaublomme D, Browaeys R, Scott C, Martens L . Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche. Immunity. 2019; 51(4):638-654.e9. PMC: 6876284. DOI: 10.1016/j.immuni.2019.08.017. View

Belkina A, Denis G . BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012; 12(7):465-77. PMC: 3934568. DOI: 10.1038/nrc3256. View

Kaikkonen M, Spann N, Heinz S, Romanoski C, Allison K, Stender J . Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013; 51(3):310-25. PMC: 3779836. DOI: 10.1016/j.molcel.2013.07.010. View

Ito A, Hong C, Rong X, Zhu X, Tarling E, Hedde P . LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife. 2015; 4:e08009. PMC: 4517437. DOI: 10.7554/eLife.08009. View

Wang K, Chang H . Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011; 43(6):904-14. PMC: 3199020. DOI: 10.1016/j.molcel.2011.08.018. View

Yu S, Li S, Henke A, Muse E, Cheng B, Welzel G . Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. FASEB J. 2016; 30(7):2570-9. PMC: 4904286. DOI: 10.1096/fj.201600244R. View

Janowski B, Willy P, Devi T, Falck J, Mangelsdorf D . An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996; 383(6602):728-31. DOI: 10.1038/383728a0. View

10.

Mossanen J, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T . Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology. 2016; 64(5):1667-1682. DOI: 10.1002/hep.28682. View

11.

Hernandez G, Luo T, Javed T, Wen L, Kalwat M, Vale K . Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy. Sci Transl Med. 2020; 12(525). PMC: 7034981. DOI: 10.1126/scitranslmed.aay5186. View

12.

Boyes J, Felsenfeld G . Tissue-specific factors additively increase the probability of the all-or-none formation of a hypersensitive site. EMBO J. 1996; 15(10):2496-507. PMC: 450182. View

13.

Hotamisligil G . Endoplasmic reticulum stress and atherosclerosis. Nat Med. 2010; 16(4):396-9. PMC: 2897068. DOI: 10.1038/nm0410-396. View

14.

Seidman J, Troutman T, Sakai M, Gola A, Spann N, Bennett H . Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis. Immunity. 2020; 52(6):1057-1074.e7. PMC: 7305990. DOI: 10.1016/j.immuni.2020.04.001. View

15.

Zhang Y, Leung D, Richers B, Liu Y, Remigio L, Riches D . Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012; 188(5):2127-35. PMC: 3368346. DOI: 10.4049/jimmunol.1102412. View

16.

Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K . Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol. 2010; 46(1):101-7. DOI: 10.1007/s00535-010-0291-8. View

17.

Horvath S, Raj K . DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6):371-384. DOI: 10.1038/s41576-018-0004-3. View

18.

Wang X, Cai B, Yang X, Sonubi O, Zheng Z, Ramakrishnan R . Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metab. 2020; 31(5):969-986.e7. PMC: 7313619. DOI: 10.1016/j.cmet.2020.03.010. View

19.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

20.

Mridha A, Wree A, Robertson A, Yeh M, Johnson C, Van Rooyen D . NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017; 66(5):1037-1046. PMC: 6536116. DOI: 10.1016/j.jhep.2017.01.022. View