p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli

Aging

Volumn 9, Issue 8, 2017, Pages 1867-1884

  Hall, Brandon M ^a   Balan, Vitaly ^a   Gleiberman, Anatoli S ^a   Strom, Evguenia ^a   Krasnov, Peter ^a   Virtuoso, Lauren P ^a   Rydkina, Elena ^a   Vujcic, Slavoljub ^a   Balan, Karina ^a   Gitlin, Ilya I ^b   Leonova, Katerina I ^b   Consiglio, Camila R ^b   Gollnick, Sandra O ^b   Chernova, Olga B ^a   Gudkov, Andrei V ^a,b  

^a Everon Biosciences   (United States)

^b ROSWELL PARK CANCER INSTITUTE   (United States)

Author keywords

Aging; Beta galactosidase; Macrophage; P16(Ink4a); Senescent cell

Indexed keywords

BETA GALACTOSIDASE; BIOLOGICAL MARKER; CDKN2A PROTEIN, MOUSE; CYCLIN DEPENDENT KINASE INHIBITOR 2A; IMMUNOLOGIC FACTOR; PROTEIN P53;

ADIPOSE TISSUE; AGING; ANIMAL; C57BL MOUSE; CELL AGING; CELL CULTURE; CELL PROLIFERATION; COMPARATIVE STUDY; CYTOLOGY; DRUG EFFECT; ENZYMOLOGY; GENETICS; GENOTYPE; MACROPHAGE ACTIVATION; MESENCHYMAL STROMA CELL; METABOLISM; PERITONEUM MACROPHAGE; PHENOTYPE; SIGNAL TRANSDUCTION; TIME FACTOR; TRANSGENIC MOUSE;

ADIPOSE TISSUE; AGING; ANIMALS; BETA-GALACTOSIDASE; BIOMARKERS; CELL PROLIFERATION; CELLS, CULTURED; CELLULAR SENESCENCE; CYCLIN-DEPENDENT KINASE INHIBITOR P16; GENOTYPE; IMMUNOLOGIC FACTORS; MACROPHAGE ACTIVATION; MACROPHAGES, PERITONEAL; MESENCHYMAL STROMAL CELLS; MICE, INBRED C57BL; MICE, TRANSGENIC; PHENOTYPE; SIGNAL TRANSDUCTION; TIME FACTORS; TUMOR SUPPRESSOR PROTEIN P53;

EID: 85028598149     PISSN: 19454589     EISSN: None     Source Type: Journal    
DOI: 10.18632/aging.101268     Document Type: Article

References (78)

1. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. https://doi.org/10.1146/annurev-pathol-121808-102144
2. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010; 24:2463-
3. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6:2853-
4. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007; 128:92-105. https://doi.org/10.1016/j.mad.2006.11.016
5. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908:244-54. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
6. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to ageassociated diseases. J Gerontol A Biol Sci Med Sci. 2014 (Suppl 1); 69:S4-9. https://doi.org/10.1093/gerona/glu057
7. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014; 17:324-28. https://doi.org/10.1097/MCO.0000000000000065
8. Cevenini E, Monti D, Franceschi C. Inflamm-ageing. Curr Opin Clin Nutr Metab Care. 2013; 16:14-20. https://doi.org/10.1097/MCO.0b013e32835ada13
9. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev. 2009; 8:18-30. https://doi.org/10.1016/j.arr.2008.07.002
10. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479:232-
11. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530:184-89. https://doi.org/10.1038/nature16932
12. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016; 354:472-77. https://doi.org/10.1126/science.aaf6659
13. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016; 22:78-83. https://doi.org/10.1038/nm.4010
14. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016; 15:973-77. https://doi.org/10.1111/acel.12458
15. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016; 15:428-35. https://doi.org/10.1111/acel.12445
16. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14:644-58. https://doi.org/10.1111/acel.12344
17. Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015; 15:397-408. https://doi.org/10.1038/nrc3960
18. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocket M, Campisi J, Pardee AB. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995; 92:9363-67. https://doi.org/10.1073/pnas.92.20.9363
19. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114:1299-307 https://doi.org/10.1172/JCI22475
20. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88:593-602. https://doi.org/10.1016/S0092-8674(00)81902-9
21. Sorrentino JA, Krishnamurthy J, Tilley S, Alb JG Jr, Burd CE, Sharpless NE. p16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J Clin Invest. 2014; 124:169-73. https://doi.org/10.1172/JCI70960
22. Burd CE, Sorrentino JA, Clark KS, Darr DB, Krishnamurthy J, Deal AM, Bardeesy N, Castrillon DH, Beach DH, Sharpless NE. Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell. 2013; 152:340-51. https://doi.org/10.1016/j.cell.2012.12.010
23. Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A, Chernova OB, Gudkov AV. Aging of mice is associated with p16(Ink4α)-and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY). 2016; 8:1294-315. https://doi.org/10.18632/aging.100991
24. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013; 496:445-55. https://doi.org/10.1038/nature12034
25. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016; 44:450-
26. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004; 25:677-86. https://doi.org/10.1016/j.it.2004.09.015
27. Roszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm. 2015; 2015:816460. https://doi.org/10.1155/2015/816460
28. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. https://doi.org/10.12703/P6-13
29. Murray PJ. Macrophage Polarization. Annu Rev Physiol. 2017; 79:541-66. https://doi.org/10.1146/annurev-physiol-022516-034339
30. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004; 4:71-78. https://doi.org/10.1038/nrc1256
31. Jackaman C, Radley-Crabb HG, Soffe Z, Shavlakadze T, Grounds MD, Nelson DJ. Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice. Aging Cell. 2013; 12:345-57. https://doi.org/10.1111/acel.12062
32. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011; 145:341-55. https://doi.org/10.1016/j.cell.2011.04.005
33. Jonsdottir G, Ingolfsdottir IE, Thormodsson FR, Petersen PH, Aisen PS, Ashe KH, Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, et al. Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response. Neurobiol Aging. 2013; 34:1389-96. https://doi.org/10.1016/j.neurobiolaging.2012.11.012
34. Bu L, Gao M, Qu S, Liu D. Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J. 2013; 15:1001-11. https://doi.org/10.1208/s12248-013-9501-7
35. Feng B, Jiao P, Nie Y, Kim T, Jun D, van Rooijen N, Yang Z, Xu H. Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice. PLoS One. 2011; 6:e24358. https://doi.org/10.1371/journal.pone.0024358
36. Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 2008; 8:301-09. https://doi.org/10.1016/j.cmet.2008.08.015
37. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016; 44:450-
38. Li H, You H, Fan X, Jia J. Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets. BMJ open Gastroenterol. 2016; 3: e000079. https://doi.org/10.1136/bmjgast-2016-000079
39. Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol. 2015; 6:602. https://doi.org/10.3389/fimmu.2015.00602
40. Sun AR, Friis T, Sekar S, Crawford R, Xiao Y, Prasadam I. Is Synovial Macrophage Activation the Inflammatory Link Between Obesity and Osteoarthritis? Curr Rheumatol Rep. 2016; 18:57. https://doi.org/10.1007/s11926-016-0605-9
41. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA. 2001; 98:12072-77. https://doi.org/10.1073/pnas.211053698
42. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife. 2015; 4:e12997. https://doi.org/10.7554/eLife.12997
43. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017; 8:14532. https://doi.org/10.1038/ncomms14532
44. Wang P, Du H, Zhang RY, Guan YF, Xu TY, Xu QY, Su DF, Miao CY. Circulating and local visfatin/Nampt/PBEF levels in spontaneously hypertensive rats, stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats. J Physiol Sci. 2010; 60:317-24. https://doi.org/10.1007/s12576-010-0103-1
45. Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017; 23:775-81. https://doi.org/10.1038/nm.4324
46. Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013; 32:5129-43. https://doi.org/10.1038/onc.2012.640
47. Itahana K, Dimri G, Campisi J. Regulation of cellular senescence by p53. Eur J Biochem. 2001; 268:2784-91. https://doi.org/10.1046/j.1432-1327.2001.02228.x
48. Le ON, Rodier F, Fontaine F, Coppe JP, Campisi J, DeGregori J, Laverdière C, Kokta V, Haddad E, Beauséjour CM. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell. 2010; 9:398-409. https://doi.org/10.1111/j.1474-9726.2010.00567.x
49. Lorimore SA, Coates PJ, Scobie GE, Milne G, Wright EG. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiationinduced bystander effects? Oncogene. 2001; 20:7085-95. https://doi.org/10.1038/sj.onc.1204903
50. Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE, van den Berg SM, Luque-Martin R, Chen HJ, Boshuizen MC, Ahmed M, Hoeksema MA, de Vos AF, de Winther MP. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Reports. 2016; 17:684-96. https://doi.org/10.1016/j.celrep.2016.09.008
51. Cudejko C, Wouters K, Fuentes L, Hannou SA, Paquet C, Bantubungi K, Bouchaert E, Vanhoutte J, Fleury S, Remy P, Tailleux A, Chinetti-Gbaguidi G, Dombrowicz D, et al. p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. Blood. 2011; 118:2556-66. https://doi.org/10.1182/blood-2010-10-313106
52. Leonova KI, Brodsky L, Lipchick B, Pal M, Novototskaya L, Chenchik AA, Sen GC, Komarova EA, Gudkov AV. p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs. Proc Natl Acad Sci USA. 2013; 110:E89-98. https://doi.org/10.1073/pnas.1216922110
53. Zhang X, Goncalves R, Mosser DM. The Isolation and Characterization of Murine Macrophages. Curr Protoc Immunol. 2008; Chapter 14:Unit 14.1. https://doi.org/10.1002/0471142735.im1401s83
54. Bennett MR, Clarke MC. Basic research: Killing the old: cell senescence in atherosclerosis. Nat Rev Cardiol. 2016; 14:8-9. https://doi.org/10.1038/nrcardio.2016.195
55. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017; 21:21-
56. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016; 15:428-35. https://doi.org/10.1111/acel.12445
57. Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD, Tchkonia T, Kirkland JL. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017; 9:955-63
58. Johmura Y, Nakanishi M. Multiple facets of p53 in senescence induction and maintenance. Cancer Sci. 2016; 107:1550-55. https://doi.org/10.1111/cas.13060
59. Qian Y, Chen X. Senescence regulation by the p53 protein family. Methods Mol Biol. 2013; 965:37-61. https://doi.org/10.1007/978-1-62703-239-1_3
60. Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003; 22:4212-22. https://doi.org/10.1093/emboj/cdg417
61. Fuentes L, Wouters K, Hannou SA, Cudejko C, Rigamonti E, Mayi TH, Derudas B, Pattou F, Chinetti-Gbaguidi G, Staels B, Paumelle R. Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype. Diabetologia. 2011; 54:3150-56. https://doi.org/10.1007/s00125-011-2324-0
62. Murakami Y, Mizoguchi F, Saito T, Miyasaka N, Kohsaka H. p16(INK4a) exerts an anti-inflammatory effect through accelerated IRAK1 degradation in macrophages. J Immunol. 2012; 189:5066-72. https://doi.org/10.4049/jimmunol.1103156
63. Li L, Ng DS, Mah WC, Almeida FF, Rahmat SA, Rao VK, Leow SC, Laudisi F, Peh MT, Goh AM, Lim JS, Wright GD, Mortellaro A, et al. A unique role for p53 in the regulation of M2 macrophage polarization. Cell Death Differ. 2015; 22:1081-93. https://doi.org/10.1038/cdd.2014.212
64. Herranz S, Través PG, Luque A, Hortelano S. Role of the tumor suppressor ARF in macrophage polarization: enhancement of the M2 phenotype in ARF-deficient mice. OncoImmunology. 2012; 1:1227-
65. Rackov G, Hernández-Jiménez E, Shokri R, Carmona-Rodríguez L, Mañes S, álvarez-Mon M, López-Collazo E, Martínez-A C, Balomenos D. p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β. J Clin Invest. 2016; 126:3089-103. https://doi.org/10.1172/JCI83404
66. Lowe JM, Menendez D, Bushel PR, Shatz M, Kirk EL, Troester MA, Garantziotis S, Fessler MB, Resnick MA. p53 and NF-κB coregulate proinflammatory gene responses in human macrophages. Cancer Res. 2014; 74:2182-92. https://doi.org/10.1158/0008-5472.CAN-13-1070
67. Mukhopadhyay S, Antalis TM, Nguyen KP, Hoofnagle MH, Sarkar R. Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice. Blood. 2017; 129:3245-55. https://doi.org/10.1182/blood-2016-07-727180
68. Schmitz ML, Kracht M. Cyclin-dependent kinases as coregulators of inflammatory gene expression. Trends Pharmacol Sci. 2016; 37:101-13. https://doi.org/10.1016/j.tips.2015.10.004
69. Shime H, Matsumoto M, Oshiumi H, Tanaka S, Nakane A, Iwakura Y, Tahara H, Inoue N, Seya T. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc Natl Acad Sci USA. 2012; 109:2066-71. https://doi.org/10.1073/pnas.1113099109
70. Liu B, Wang X, Chen TZ, Li GL, Tan CC, Chen Y, Duan SQ. Polarization of M1 tumor associated macrophage promoted by the activation of TLR3 signal pathway. Asian Pac J Trop Med. 2016; 9:484-88. https://doi.org/10.1016/j.apjtm.2016.03.019
71. Yarilina A, Xu K, Chan C, Ivashkiv LB. Regulation of inflammatory responses in tumor necrosis factoractivated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012; 64:3856-66. https://doi.org/10.1002/art.37691
72. Brownlow N, Mol C, Hayford C, Ghaem-Maghami S, Dibb NJ. Dasatinib is a potent inhibitor of tumourassociated macrophages, osteoclasts and the FMS receptor. Leukemia. 2009; 23:590-94. https://doi.org/10.1038/leu.2008.237
73. Cruz FF, Horta LF, Maia LA, Lopes-Pacheco M, da Silva AB, Morales MM, Gonçalves-de-Albuquerque CF, Takiya CM, de Castro-Faria-Neto HC, Rocco PR. Dasatinib reduces lung inflammation and fibrosis in acute experimental silicosis. PLoS One. PLoS One. 2016; 11:e0147005. https://doi.org/10.1371/journal.pone.0147005
74. Ozanne J, Prescott AR, Clark K. The clinically approved drugs dasatinib and bosutinib induce antiinflammatory macrophages by inhibiting the saltinducible kinases. Biochem J. 2015; 465:271-79. https://doi.org/10.1042/BJ20141165
75. Sun L, Li E, Wang F, Wang T, Qin Z, Niu S, Qiu C. Quercetin increases macrophage cholesterol efflux to inhibit foam cell formation through activating PPARγ-ABCA1 pathway. Int J Clin Exp Pathol. 2015; 8:10854-60
76. De Stefano D, Maiuri MC, Simeon V, Grassia G, Soscia A, Cinelli MP, Carnuccio R. Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-γ. Eur J Pharmacol. 2007; 566:192-99. https://doi.org/10.1016/j.ejphar.2007.03.051
77. Derlindati E, Dall'Asta M, Ardigò D, Brighenti F, Zavaroni I, Crozier A, Del Rio D. Quercetin-3-Oglucuronide affects the gene expression profile of M1 and M2a human macrophages exhibiting antiinflammatory effects. Food Funct. 2012; 3:1144-52. https://doi.org/10.1039/c2fo30127j
78. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014; 31:722-33. https://doi.org/10.1016/j.devcel.2014.11.012