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The role of 27-hydroxycholesterol in meta-inflammation

  • Yonghae Son (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Eunbeen Choi (Department of Medicine, School of Medicine, Pusan National University) ;
  • Yujin Hwang (Department of Medicine, School of Medicine, Pusan National University) ;
  • Koanhoi Kim (Department of Pharmacology, School of Medicine, Pusan National University)
  • Received : 2023.11.17
  • Accepted : 2024.01.09
  • Published : 2024.03.01

Abstract

27-Hydroxycholesterol (27OHChol), a prominent cholesterol metabolite present in the bloodstream and peripheral tissues, is a kind of immune oxysterol that elicits immune response. Recent research indicates the involvement of 27OHChol in metabolic inflammation (meta-inflammation) characterized by chronic responses associated with metabolic irregularities. 27OHChol activates monocytic cells such that they secrete pro-inflammatory cytokines and chemokines, and increase the expression of cell surface molecules such as pattern-recognition receptors that play key roles in immune cell-cell communication and sensing metabolism-associated danger signals. Levels of 27OHChol increase when cholesterol metabolism is disrupted, and the resulting inflammatory responses can contribute to the development and complications of metabolic syndrome, including obesity, insulin resistance, and cardiovascular diseases. Since 27OHChol can induce chronic immune response by activating monocyte-macrophage lineage cells that play a crucial role in meta-inflammation, it is essential to understand the 27OHChol-induced inflammatory responses to unravel the roles and mechanisms of action of this cholesterol metabolite in chronic metabolic disorders.

Keywords

Acknowledgement

This work was supported by a 2-Year Research Grant of Pusan National University.

References

  1. Cortes VA, Busso D, Maiz A, Arteaga A, Nervi F, Rigotti A. Physiological and pathological implications of cholesterol. Front Biosci (Landmark Ed). 2014;19:416-428. https://doi.org/10.2741/4216
  2. Brown AJ, Jessup W. Oxysterols and atherosclerosis. Atherosclerosis. 1999;142:1-28. https://doi.org/10.1016/S0021-9150(98)00196-8
  3. Carpenter KL, Taylor SE, van der Veen C, Williamson BK, Ballantine JA, Mitchinson MJ. Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim Biophys Acta. 1995;1256:141-150. https://doi.org/10.1016/0005-2760(94)00247-V
  4. Garcia-Cruset S, Carpenter KL, Guardiola F, Stein BK, Mitchinson MJ. Oxysterol profiles of normal human arteries, fatty streaks and advanced lesions. Free Radic Res. 2001;35:31-41. https://doi.org/10.1080/10715760100300571
  5. Choi C, Finlay DK. Diverse immunoregulatory roles of oxysterols-the oxidized cholesterol metabolites. Metabolites. 2020;10:384.
  6. Schroepfer GJ Jr. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev. 2000;80:361-554. https://doi.org/10.1152/physrev.2000.80.1.361
  7. Umetani M, Shaul PW. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol Metab. 2011;22:130-135. https://doi.org/10.1016/j.tem.2011.01.003
  8. Lee J, Kim BY, Son Y, Giang DH, Lee D, Eo SK, Kim K. 4'OMethylalpinumisoflavone inhibits the activation of monocytes/macrophages to an immunostimulatory phenotype induced by 27hydroxycholesterol. Int J Mol Med. 2019;43:2177-2186.
  9. Son Y, Kim SM, Lee SA, Eo SK, Kim K. Oxysterols induce transition of monocytic cells to phenotypically mature dendritic cell-like cells. Biochem Biophys Res Commun. 2013;438:161-168. https://doi.org/10.1016/j.bbrc.2013.07.046
  10. Kim SM, Kim BY, Eo SK, Kim CD, Kim K. 27-Hydroxycholesterol up-regulates CD14 and predisposes monocytic cells to superproduction of CCL2 in response to lipopolysaccharide. Biochim Biophys Acta. 2015;1852:442-450. https://doi.org/10.1016/j.bbadis.2014.12.003
  11. Kim SM, Kim BY, Lee SA, Eo SK, Yun Y, Kim CD, Kim K. 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes. Toxicol Appl Pharmacol. 2014;274:462-470. https://doi.org/10.1016/j.taap.2013.12.007
  12. Asghari A, Ishikawa T, Hiramitsu S, Lee WR, Umetani J, Bui L, Korach KS, Umetani M. 27-Hydroxycholesterol promotes adiposity and mimics adipogenic diet-induced inflammatory signaling. Endocrinology. 2019;160:2485-2494. https://doi.org/10.1210/en.2019-00349
  13. Asghari A, Umetani M. Obesity and cancer: 27-hydroxycholesterol, the missing link. Int J Mol Sci. 2020;21:4822.
  14. Poli G, Biasi F, Leonarduzzi G. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol. 2013;1:125-130. https://doi.org/10.1016/j.redox.2012.12.001
  15. Umetani M, Ghosh P, Ishikawa T, Umetani J, Ahmed M, Mineo C, Shaul PW. The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. Cell Metab. 2014;20:172-182. https://doi.org/10.1016/j.cmet.2014.05.013
  16. Ramos-Lopez O, Martinez-Urbistondo D, Vargas-Nunez JA, Martinez JA. The role of nutrition on meta-inflammation: insights and potential targets in communicable and chronic disease management. Curr Obes Rep. 2022;11:305-335. https://doi.org/10.1007/s13679-022-00490-0
  17. d'Aiello A, Bonanni A, Vinci R, Pedicino D, Severino A, De Vita A, Filomia S, Brecciaroli M, Liuzzo G. Meta-inflammation and new anti-diabetic drugs: a new chance to knock down residual cardiovascular risk. Int J Mol Sci. 2023;24:8643.
  18. Qu L, Matz AJ, Karlinsey K, Cao Z, Vella AT, Zhou B. Macrophages at the crossroad of meta-inflammation and inflammaging. Genes (Basel). 2022;13:2074.
  19. Russo S, Kwiatkowski M, Govorukhina N, Bischoff R, Melgert BN. Meta-inflammation and metabolic reprogramming of macrophages in diabetes and obesity: the importance of metabolites. Front Immunol. 2021;12:746151.
  20. Kim BY, Son Y, Cho HR, Lee D, Eo SK, Kim K. 27-Hydroxycholesterol induces macrophage gene expression via LXR-dependent and -independent mechanisms. Korean J Physiol Pharmacol. 2021;25:111-118. https://doi.org/10.4196/kjpp.2021.25.2.111
  21. Kim SM, Lee SA, Kim BY, Bae SS, Eo SK, Kim K. 27-Hydroxycholesterol induces recruitment of monocytic cells by enhancing CCL2 production. Biochem Biophys Res Commun. 2013;442:159-164. https://doi.org/10.1016/j.bbrc.2013.11.052
  22. Chu HX, Arumugam TV, Gelderblom M, Magnus T, Drummond GR, Sobey CG. Role of CCR2 in inflammatory conditions of the central nervous system. J Cereb Blood Flow Metab. 2014;34:1425-1429. https://doi.org/10.1038/jcbfm.2014.120
  23. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11:762-774. https://doi.org/10.1038/nri3070
  24. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143. https://doi.org/10.1161/hc0902.104353
  25. Gschwandtner M, Derler R, Midwood KS. More than just attractive: how CCL2 influences myeloid cell behavior beyond chemotaxis. Front Immunol. 2019;10:2759.
  26. Kim SM, Jang H, Son Y, Lee SA, Bae SS, Park YC, Eo SK, Kim K. 27-hydroxycholesterol induces production of tumor necrosis factor-alpha from macrophages. Biochem Biophys Res Commun. 2013;430:454-459. https://doi.org/10.1016/j.bbrc.2012.12.021
  27. Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr. 2010;20:87-103. https://doi.org/10.1615/CritRevEukarGeneExpr.v20.i2.10
  28. Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett. 2008;582:117-131. https://doi.org/10.1016/j.febslet.2007.11.051
  29. Nieto-Vazquez I, Fernandez-Veledo S, Kramer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem. 2008;114:183-194. Erratum in: Arch Physiol Biochem. 2009;115:117.
  30. Kleinbongard P, Heusch G, Schulz R. TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 2010;127:295-314.
  31. Zhang Y, Yang X, Bian F, Wu P, Xing S, Xu G, Li W, Chi J, Ouyang C, Zheng T, Wu D, Zhang Y, Li Y, Jin S. TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-κB and PPAR-γ. J Mol Cell Cardiol. 2014;72:85-94. https://doi.org/10.1016/j.yjmcc.2014.02.012
  32. Popa C, Netea MG, van Riel PL, van der Meer JW, Stalenhoef AF. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res. 2007;48:751-762. https://doi.org/10.1194/jlr.R600021-JLR200
  33. Kim SM, Lee CW, Kim BY, Jung YS, Eo SK, Park YC, Kim K. 27-Oxygenated cholesterol induces expression of CXCL8 in macrophages via NF-κB and CD88. Biochem Biophys Res Commun. 2015;463:1152-1158. https://doi.org/10.1016/j.bbrc.2015.06.075
  34. Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol. 2023;20:217-251. https://doi.org/10.1038/s41423-023-00974-6
  35. Apostolakis S, Vogiatzi K, Amanatidou V, Spandidos DA. Interleukin 8 and cardiovascular disease. Cardiovasc Res. 2009;84:353-360. https://doi.org/10.1093/cvr/cvp241
  36. Silva BRD, Cirelli T, Nepomuceno R, Theodoro LH, Orrico SRP, Cirelli JA, Barros SP, Scarel-Caminaga RM. Functional haplotype in the interleukin8 (CXCL8) gene is associated with type 2 diabetes mellitus and periodontitis in Brazilian population. Diabetes Metab Syndr. 2020;14:1665-1672.
  37. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344-345.
  38. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999;5:285-294. https://doi.org/10.1097/00054725-199911000-00009
  39. Chen J, Xiang X, Nie L, Guo X, Zhang F, Wen C, Xia Y, Mao L. The emerging role of Th1 cells in atherosclerosis and its implications for therapy. Front Immunol. 2023;13:1079668.
  40. Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17:387-401. https://doi.org/10.1038/s41569-020-0352-5
  41. Taleb S. Inflammation in atherosclerosis. Arch Cardiovasc Dis. 2016;109:708-715. https://doi.org/10.1016/j.acvd.2016.04.002
  42. Van Herck MA, Weyler J, Kwanten WJ, Dirinck EL, De Winter BY, Francque SM, Vonghia L. The differential roles of T cells in nonalcoholic fatty liver disease and obesity. Front Immunol. 2019;10:82.
  43. Wang Q, Wang Y, Xu D. The roles of T cells in obese adipose tissue inflammation. Adipocyte. 2021;10:435-445. https://doi.org/10.1080/21623945.2021.1965314
  44. Mahlangu T, Dludla PV, Nyambuya TM, Mxinwa V, Mazibuko-Mbeje SE, Cirilli I, Marcheggiani F, Tiano L, Louw J, Nkambule BB. A systematic review on the functional role of Th1/Th2 cytokines in type 2 diabetes and related metabolic complications. Cytokine. 2020;126:154892.
  45. Kim BY, Son Y, Choi J, Eo SK, Park YC, Kim K. 27-Hydroxycholesterol upregulates the production of heat shock protein 60 of monocytic cells. J Steroid Biochem Mol Biol. 2017;172:29-35. https://doi.org/10.1016/j.jsbmb.2017.04.015
  46. Son Y, Kim BY, Park YC, Eo SK, Cho HR, Kim K. PI3K and ERK signaling pathways are involved in differentiation of monocytic cells induced by 27-hydroxycholesterol. Korean J Physiol Pharmacol. 2017;21:301-308. https://doi.org/10.4196/kjpp.2017.21.3.301
  47. Heo W, Kim SM, Eo SK, Rhim BY, Kim K. FSL-1, a Toll-like receptor 2/6 agonist, induces expression of interleukin-1α in the presence of 27-hydroxycholesterol. Korean J Physiol Pharmacol. 2014;18:475-480. https://doi.org/10.4196/kjpp.2014.18.6.475
  48. Malik A, Kanneganti TD. Function and regulation of IL-1α in inflammatory diseases and cancer. Immunol Rev. 2018;281:124-137. https://doi.org/10.1111/imr.12615
  49. Tahtinen S, Tong AJ, Himmels P, Oh J, Paler-Martinez A, Kim L, Wichner S, Oei Y, McCarron MJ, Freund EC, Amir ZA, de la Cruz CC, Haley B, Blanchette C, Schartner JM, Ye W, Yadav M, Sahin U, Delamarre L, Mellman I. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat Immunol. 2022;23:532-542. https://doi.org/10.1038/s41590-022-01160-y
  50. Baumann CL, Aspalter IM, Sharif O, Pichlmair A, Bluml S, Grebien F, Bruckner M, Pasierbek P, Aumayr K, Planyavsky M, Bennett KL, Colinge J, Knapp S, Superti-Furga G. CD14 is a coreceptor of Toll-like receptors 7 and 9. J Exp Med. 2010;207:2689-2701. https://doi.org/10.1084/jem.20101111
  51. Choi J, Kim BY, Son Y, Lee D, Hong YS, Kim MS, Kim K. Reblastatins inhibit phenotypic changes of monocytes/macrophages in a milieu rich in 27-hydroxycholesterol. Immune Netw. 2020;20:e17.
  52. Kim BY, Son Y, Kim MS, Kim K. Prednisolone suppresses the immunostimulatory effects of 27-hydroxycholesterol. Exp Ther Med. 2020;19:2335-2342.
  53. Kim BY, Son Y, Lee J, Choi J, Kim CD, Bae SS, Eo SK, Kim K. Dexamethasone inhibits activation of monocytes/macrophages in a milieu rich in 27-oxygenated cholesterol. PLoS One. 2017;12:e0189643.
  54. Kang YE, Joung KH, Kim JM, Lee JH, Kim HJ, Ku BJ. Serum CD14 concentration is associated with obesity and insulin resistance in non-diabetic individuals. J Int Med Res. 2022;50:3000605221130010.
  55. Leite F, Leite A, Santos A, Lima M, Barbosa J, Cosentino M, Ribeiro L. Predictors of subclinical inflammatory obesity: plasma levels of leptin, very low-density lipoprotein cholesterol and CD14 expression of CD16+ monocytes. Obes Facts. 2017;10:308-322. https://doi.org/10.1159/000464294
  56. Duan J, Liu H, Chen J, Li X, Li P, Zhang R. Changes in gene expression of adipose tissue CD14+ cells in patients with Type 2 diabetes mellitus and their relationship with environmental factors. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021;46:1-10.
  57. Wu Z, Zhang Z, Lei Z, Lei P. CD14: biology and role in the pathogenesis of disease. Cytokine Growth Factor Rev. 2019;48:24-31. https://doi.org/10.1016/j.cytogfr.2019.06.003
  58. Bjorkhem I, Leitersdorf E. Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans. Trends Endocrinol Metab. 2000;11:180-183. https://doi.org/10.1016/S1043-2760(00)00255-1