Dysregulation of macrophage development and phenotype in diabetic human macrophages can be rescued by Hoxa3 protein transduction
Autoři:
Salma Alrdahe aff001; Hadeel Al Sadoun aff002; Tanja Torbica aff001; Edward A. McKenzie aff003; Frank L. Bowling aff004; Andrew J. M. Boulton aff004; Kimberly A. Mace aff001
Působiště autorů:
Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
aff001; Stem Cell Unit, King Fahad Medical Research Center, Department of Laboratory Medical Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Saudi Arabia
aff002; Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom
aff003; Division of Diabetes, Endocrinology & Gastroenterology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
aff004
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0223980
Souhrn
Controlled inflammatory responses of myeloid cells recruited to wounds are essential for effective repair. In diabetes, the inflammatory response is prolonged and augmented over time, with increased myeloid cells present in the wound that fail to switch from a pro-inflammatory phenotype to a pro-healing phenotype. These defects lead to delayed angiogenesis and tissue repair and regeneration, and contribute to chronic wound formation. In mouse models of diabetes, this aberrant phenotype is partially mediated by stable intrinsic changes to the developing myeloid cells in the bone marrow, affecting their maturation and polarization potential. Previous studies have shown that freshly isolated peripheral blood mononuclear cells from diabetic patients are more inflammatory than non-diabetic counterparts. However, the phenotype of macrophages from human diabetic patients has not been well characterized. Here we show that diabetic-derived human macrophages cultured for 6 days in vitro maintain a pro-inflammatory priming and hyperpolarize to a pro-inflammatory phenotype when stimulated with LPS and INF-ɣ or TNF. In addition, diabetic-derived macrophages show maturation defects associated with reduced expression of the RUNX1 transcription factor that promotes myeloid cell development. Targeting intrinsic defects in myeloid cells by protein transduction of the Hoxa3 transcription factor can rescue some inflammation and maturation defects in human macrophages from diabetic patients via upregulation of Runx1. In addition, Hoxa3 can modulate the levels of p65/NF-κB and histone acetyltransferase and deacetylase activity, as well as inhibit acetylation of the TNF promoter. Altogether, these results show a link between myeloid cell maturation and inflammatory responses, and that diabetes induces intrinsic changes to human myeloid cells that are maintained over time, as well as potentially therapeutic Hoxa3-mediated mechanisms of controlling the inflammatory response in diabetes.
Klíčová slova:
Cell differentiation – Transcription factors – Cytokines – Inflammation – Macrophages – Monocytes – Bone marrow cells
Zdroje
1. Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R, Nusgart M, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Health. 2018;21: 27–32. doi: 10.1016/j.jval.2017.07.007 29304937
2. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117: 1219–1222. doi: 10.1172/JCI32169 17476353
3. Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2015;4: 560–582. doi: 10.1089/wound.2015.0635 26339534
4. Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry WL, Albina JE. The monocyte to macrophage transition in the murine sterile wound. PLoS ONE. 2014;9: e86660. doi: 10.1371/journal.pone.0086660 24466192
5. Daley JM, Brancato SK, Thomay AA, Reichner JS, Albina JE. The phenotype of murine wound macrophages. J Leukoc Biol. 2010;87: 59–67. doi: 10.1189/jlb.0409236 20052800
6. Ferrante CJ, Leibovich SJ. Regulation of Macrophage Polarization and Wound Healing. Adv Wound Care (New Rochelle). 2012;1: 10–16. doi: 10.1089/wound.2011.0307 24527272
7. Jetten N, Roumans N, Gijbels MJ, Romano A, Post MJ, de Winther MPJ, et al. Wound Administration of M2-Polarized Macrophages Does Not Improve Murine Cutaneous Healing Responses. PLoS One. 2014;9. doi: 10.1371/journal.pone.0102994 25068282
8. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184: 3964–3977. doi: 10.4049/jimmunol.0903356 20176743
9. Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, et al. Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice. PLoS ONE. 2010;5. doi: 10.1371/journal.pone.0009539 20209061
10. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23: 549–555. 12401408
11. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164: 6166–6173. doi: 10.4049/jimmunol.164.12.6166 10843666
12. Bannon P, Wood S, Restivo T, Campbell L, Hardman MJ, Mace KA. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. Dis Model Mech. 2013;6: 1434–1447. doi: 10.1242/dmm.012237 24057002
13. Miao M, Niu Y, Xie T, Yuan B, Qing C, Lu S. Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation. Wound Repair Regen. 2012;20: 203–213. doi: 10.1111/j.1524-475X.2012.00772.x 22380690
14. Mirza R, Koh TJ. Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine. 2011;56: 256–264. doi: 10.1016/j.cyto.2011.06.016 21803601
15. Wicks K, Torbica T, Mace KA. Myeloid cell dysfunction and the pathogenesis of the diabetic chronic wound. Semin Immunol. 2014;26: 341–353. doi: 10.1016/j.smim.2014.04.006 24954378
16. Wicks K, Torbica T, Umehara T, Amin S, Bobola N, Mace KA. Diabetes Inhibits Gr-1+ Myeloid Cell Maturation via Cebpa Deregulation. Diabetes. 2015;64: 4184–4197. doi: 10.2337/db14-1895 26324181
17. Kraakman MJ, Murphy AJ, Jandeleit-Dahm K, Kammoun HL. Macrophage Polarization in Obesity and Type 2 Diabetes: Weighing Down Our Understanding of Macrophage Function? Front Immunol. 2014;5. doi: 10.3389/fimmu.2014.00470 25309549
18. Mace KA, Hansen SL, Myers C, Young DM, Boudreau N. HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair. J Cell Sci. 2005;118: 2567–2577. doi: 10.1242/jcs.02399 15914537
19. Al Sadoun H, Burgess M, Hentges KE, Mace KA. Enforced Expression of Hoxa3 Inhibits Classical and Promotes Alternative Activation of Macrophages In Vitro and In Vivo. J Immunol. 2016;197: 872–884. doi: 10.4049/jimmunol.1501944 27342843
20. Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo P-H, et al. Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nature medicine. 2003;9: 1423–1427. doi: 10.1038/nm953 14578882
21. Derossi D, Calvet S, Trembleau A, Brunissen A, Chassaing G, Prochiantz A. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J Biol Chem. 1996;271: 18188–18193. doi: 10.1074/jbc.271.30.18188 8663410
22. Mahdipour E, Charnock JC, Mace KA. Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells. Blood. 2011;117: 815–826. doi: 10.1182/blood-2009-12-259549 20974673
23. Moeenrezakhanlou A, Shephard L, Lam L, Reiner NE. Myeloid cell differentiation in response to calcitriol for expression CD11b and CD14 is regulated by myeloid zinc finger-1 protein downstream of phosphatidylinositol 3-kinase. J Leukoc Biol. 2008;84: 519–528. doi: 10.1189/jlb.1207833 18495781
24. Caprodossi S, Pedinotti M, Amantini C, Santoni G, Minucci S, Pelicci PG, et al. Differentiation response of acute promyelocytic leukemia cells and PML/RARa leukemogenic activity studies by real-time RT-PCR. Mol Biotechnol. 2005;30: 231–238. 15988048
25. Maess MB, Sendelbach S, Lorkowski S. Selection of reliable reference genes during THP-1 monocyte differentiation into macrophages. BMC Mol Biol. 2010;11: 90. doi: 10.1186/1471-2199-11-90 21122122
26. Mace KA, Restivo TE, Rinn JL, Paquet AC, Chang HY, Young DM, et al. HOXA3 modulates injury-induced mobilization and recruitment of bone marrow-derived cells. Stem Cells. 2009;27: 1654–1665. doi: 10.1002/stem.90 19544454
27. Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996;4: 411–420. doi: 10.1046/j.1524-475X.1996.40404.x 17309691
28. Mirza RE, Fang MM, Weinheimer-Haus EM, Ennis WJ, Koh TJ. Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice. Diabetes. 2014;63: 1103–1114. doi: 10.2337/db13-0927 24194505
29. Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol. 2000;115: 245–253. doi: 10.1046/j.1523-1747.2000.00029.x 10951242
30. Antonchuk J, Sauvageau G, Humphries RK. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell. 2002;109: 39–45. doi: 10.1016/s0092-8674(02)00697-9 11955445
31. Sunderkötter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004;172: 4410–4417. doi: 10.4049/jimmunol.172.7.4410 15034056
32. Wallace HJ, Stacey MC. Levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in chronic venous leg ulcers—correlations to healing status. J Invest Dermatol. 1998;110: 292–296. doi: 10.1046/j.1523-1747.1998.00113.x 9506452
33. Hübner G, Brauchle M, Smola H, Madlener M, Fässler R, Werner S. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine. 1996;8: 548–556. doi: 10.1006/cyto.1996.0074 8891436
34. Kaiser GC, Polk DB. Tumor necrosis factor alpha regulates proliferation in a mouse intestinal cell line. Gastroenterology. 1997;112: 1231–1240. doi: 10.1016/s0016-5085(97)70135-5 9098007
35. Chan YC, Roy S, Khanna S, Sen CK. Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2. Arterioscler Thromb Vasc Biol. 2012;32: 1372–1382. doi: 10.1161/ATVBAHA.112.248583 22499991
36. Siqueira MF, Li J, Chehab L, Desta T, Chino T, Krothpali N, et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia. 2010;53: 378–388. doi: 10.1007/s00125-009-1529-y 19902175
37. Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, Lorenzo M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes. 2008;57: 3211–3221. doi: 10.2337/db07-1062 18796617
38. Drifte G, Dunn-Siegrist I, Tissières P, Pugin J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med. 2013;41: 820–832. doi: 10.1097/CCM.0b013e318274647d 23348516
39. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38: 576–589. doi: 10.1016/j.molcel.2010.05.004 20513432
40. Kaikkonen MU, Spann NJ, Heinz S, Romanoski CE, Allison KA, Stender JD, et al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013;51: 310–325. doi: 10.1016/j.molcel.2013.07.010 23932714
41. Gangenahalli GU, Gupta P, Saluja D, Verma YK, Kishore V, Chandra R, et al. Stem cell fate specification: role of master regulatory switch transcription factor PU.1 in differential hematopoiesis. Stem Cells Dev. 2005;14: 140–152. doi: 10.1089/scd.2005.14.140 15910240
42. Valledor AF, Borràs FE, Cullell-Young M, Celada A. Transcription factors that regulate monocyte/macrophage differentiation. J Leukoc Biol. 1998;63: 405–417. doi: 10.1002/jlb.63.4.405 9544570
43. Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int. 2013;2013: 754802. doi: 10.1155/2013/754802 23484152
44. Li P, Leonard WJ. Chromatin Accessibility and Interactions in the Transcriptional Regulation of T Cells. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.02738 30524449
45. Ramirez RN, El-Ali NC, Mager MA, Wyman D, Conesa A, Mortazavi A. Dynamic gene regulatory networks of human myeloid differentiation. Cell Syst. 2017;4: 416–429.e3. doi: 10.1016/j.cels.2017.03.005 28365152
46. Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA. Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann Rheum Dis. 2012;71: 424–431. doi: 10.1136/ard.2011.154211 21953341
Článok vyšiel v časopise
PLOS One
2019 Číslo 10
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Nejasný stín na plicích – kazuistika
- Masturbační chování žen v ČR − dotazníková studie
- Je Fuchsova endotelová dystrofie rohovky neurodegenerativní onemocnění?
- Fixní kombinace paracetamol/kodein nabízí synergické analgetické účinky
Najčítanejšie v tomto čísle
- Correction: Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study
- Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity
- Prevalence of pectus excavatum (PE), pectus carinatum (PC), tracheal hypoplasia, thoracic spine deformities and lateral heart displacement in thoracic radiographs of screw-tailed brachycephalic dogs
- Risk factors associated with IgA vasculitis with nephritis (Henoch–Schönlein purpura nephritis) progressing to unfavorable outcomes: A meta-analysis