Современные представления об этиологии и патогенезе воспалительных заболеваний кишечника (Часть 1): роль иммунной системы, генетических и эпигенетических факторов

Воспалительные заболевания кишечника (ВЗК) в последние годы в клинической практике и становятся предметом многочисленных научных исследований. Настоящий обзор подробно рассматривает ключевые аспекты патогенеза ВЗК, включая роль иммунной системы, стромальных компонентов и генетических факторов. Особое внимание уделяется взаимодействию этих факторов и их влиянию на развитие и течение заболевания. Данный обзор стремится предоставить комплексное понимание механизмов развития ВЗК и выявить потенциальные направления для диагностики, терапии и профилактики. Основное содержание статьи охватывает последние научные данные и клинические наблюдения в области гастроэнтерологии, делая акцент на интеграции различных дисциплин в понимании и лечении ВЗК.

воспалительные заболевания кишечника, болезнь Крона, язвенный колит, патогенезе, иммунная система, стромальное окружение, генетические факторы, обуславливающие ВЗК

1. Stagg A. J.Intestinal Dendritic Cells in Health and Gut Inflammation. Front Immunol. 2018 Dec 6;9:2883. doi: 10.3389/fimmu.2018.02883.

2. Grainger J.R., Konkel J. E., Zangerle-Murray T., Shaw T. N. Macrophages in gastrointestinal homeostasis and inflammation. Pflugers Arch. 2017 Apr;469(3-4):527-539. doi: 10.1007/s00424-017-1958-2.

3. Nikolakis D., de Voogd F. A.E., Pruijt M. J., Grootjans J., van de Sande M. G., D’Haens G. R. The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease.Int J Mol Sci. 2022 Feb 6;23(3):1854. doi: 10.3390/ijms23031854.

4. Baba N., Van V. Q., Wakahara K. et al. CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF. J Exp Med. 2013 Jun 3;210(6):1251-63. doi: 10.1084/jem.20122037.

5. Bsat M., Chapuy L., Baba N., Rubio M., Panzini B., Wassef R., Richard C., Soucy G., Mehta H., Sarfati M. Differential accumulation and function of proinflammatory 6-sulfo LacNAc dendritic cells in lymph node and colon of Crohn’s versus ulcerative colitis patients. J Leukoc Biol. 2015 Oct;98(4):671-81. doi: 10.1189/jlb.5A1014-509RR.

6. Mann E.R., Bernardo D., Ng S. C. et al. Human gut dendritic cells drive aberrant gut-specific t-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFNγ. Inflamm Bowel Dis. 2014 Dec;20(12):2299-307. doi: 10.1097/MIB.0000000000000223.

7. Kourepini E., Aggelakopoulou M., Alissafi T., Paschalidis N., Simoes D. C., Panoutsakopoulou V. Osteopontin expression by CD103- dendritic cells drives intestinal inflammation. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9): E856-65. doi: 10.1073/pnas.1316447111.

8. Do J.S., Visperas A., Freeman M. L., Iwakura Y., Oukka M., Min B. Colitogenic effector T cells: roles of gut-homing integrin, gut antigen specificity and γδ T cells. Immunol Cell Biol. 2014 Jan;92(1):90-8. doi: 10.1038/icb.2013.70.

9. Cai Z., Zhang W., Li M., Yue Y., Yang F., Yu L., Cao X., Wang J. TGF-beta1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4(+)Foxp3(+) regulatory T cells. Cell Mol Immunol. 2010 Jan;7(1):35-43. doi: 10.1038/cmi.2009.107. Erratum in: Cell Mol Immunol. 2020 Feb;17(2):190-191. PMID: 20081874.

10. Dörk R., Pelczar P., Shiri A. M. et al. Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility. J Crohns Colitis. 2023 Nov 24;17(11):1858-1869. doi: 10.1093/ecco-jcc/jjad103.

11. Zhou L., Yan Z., Yang W., Buckley J. A., Al Diffalha S., Benveniste E. N., Qin H. Socs3 expression in myeloid cells modulates the pathogenesis of dextran sulfate sodium (DSS)-induced colitis. Front Immunol. 2023 May 22;14:1163987. doi: 10.3389/fimmu.2023.1163987.

12. Hostmann A., Kapp K., Beutner M. et al. Dendritic cells from human mesenteric lymph nodes in inflammatory and non-inflammatory bowel diseases: subsets and function of plasmacytoid dendritic cells. Immunology. 2013 May;139(1):100-8. doi: 10.1111/imm.12060.

13. Li Q., Wang D., Hao S., Han X., Xia Y., Li X., Chen Y., Tanaka M., Qiu C. H. CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis. Front Immunol. 2017 Jun 26;8:669. doi: 10.3389/fimmu.2017.00669.

14. Korta A., Kula J., Gomułka K. The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease.Int J Mol Sci. 2023 Jun 15;24(12):10172. doi: 10.3390/ijms241210172.

15. Neurath M.F. IL-23 in inflammatory bowel diseases and colon cancer. Cytokine Growth Factor Rev. 2019 Feb;45:1-8. doi: 10.1016/j.cytogfr.2018.12.002.

16. Chapuy L., Bsat M., Rubio M. et al. Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes Reveal Differences Between Ulcerative Colitis and Crohn’s Disease. J Crohns Colitis. 2020 Mar 13;14(3):393-405. doi: 10.1093/ecco-jcc/jjz156.

17. Chapuy L., Bsat M., Mehta H. et al. Basophils increase in Crohn disease and ulcerative colitis and favor mesenteric lymph node memory TH17/TH1 response. J Allergy Clin Immunol. 2014 Oct;134(4):978-81.e1. doi: 10.1016/j.jaci.2014.05.025.

18. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E.Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209-20. doi: 10.1084/jem.174.5.1209.

19. Akdis C.A., Joss A., Akdis M., Faith A., Blaser K. A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J. 2000 Sep;14(12):1666-8. doi: 10.1096/fj.99-0874fje.

20. Joss A., Akdis M., Faith A., Blaser K., Akdis C. A. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol. 2000 Jun;30(6):1683-90. doi: 10.1002/1521-4141(200006)30:6<1683:: AID-IMMU1683>3.0.CO;2-A.

21. Opp M.R., Smith E. M., Hughes T. K. Jr.Interleukin-10 (cytokine synthesis inhibitory factor) acts in the central nervous system of rats to reduce sleep. J Neuroimmunol. 1995 Jul;60(1-2):165-8. doi: 10.1016/0165-5728(95)00066-b.

22. Aste-Amezaga M., Ma X., Sartori A., Trinchieri G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol. 1998 Jun 15;160(12):5936-44.

23. Varma T.K., Toliver-Kinsky T.E., Lin C. Y., Koutrouvelis A. P., Nichols J. E., Sherwood E. R. Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice. Infect Immun. 2001 Sep;69(9):5249-63. doi: 10.1128/IAI.69.9.5249-5263.2001.

24. Saraiva M., O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010 Mar;10(3):170-81. doi: 10.1038/nri2711.

25. Bsat M., Chapuy L., Rubio M. et al. Differential Pathogenic Th17 Profile in Mesenteric Lymph Nodes of Crohn’s Disease and Ulcerative Colitis Patients. Front Immunol. 2019 May 28;10:1177. doi: 10.3389/fimmu.2019.01177.

26. Guo X., Guo R., Luo X., Zhou L. Ethyl pyruvate ameliorates experimental colitis in mice by inhibiting the HMGB1-Th17 and Th1/Tc1 responses.Int Immunopharmacol. 2015 Dec;29(2):454-461. doi: 10.1016/j.intimp.2015.10.015.

27. Igaki K., Nakamura Y., Komoike Y. et al. Pharmacological Evaluation of TAK-828F, a Novel Orally Available RORγt Inverse Agonist, on Murine Colitis Model. Inflammation. 2019 Feb;42(1):91-102. doi: 10.1007/s10753-018-0875-7.

28. Zhang H., Wu H., Liu L., Li H., Shih D. Q., Zhang X. 1,25-dihydroxyvitamin D3 regulates the development of chronic colitis by modulating both T helper (Th)1 and Th17 activation. APMIS. 2015 Jun;123(6):490-501. doi: 10.1111/apm.12378.

29. Hu S., Chen M., Wang Y. et al. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile. PLoS One. 2016 Apr 29;11(4): e0154564. doi: 10.1371/journal.pone.0154564.

30. Liu X.J., Yu R., Zou K. F. Probiotic Mixture VSL#3 Alleviates Dextran Sulfate Sodium-induced Colitis in Mice by Downregulating T Follicular Helper Cells. Curr Med Sci. 2019 Jun;39(3):371-378. doi: 10.1007/s11596-019-2045-z.

31. Zhang R., Qi C. F., Hu Y., Shan Y. et al. T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation. J Autoimmun. 2019 Jan;96:113-122. doi: 10.1016/j.jaut.2018.09.001.

32. Chao G., Li X., Ji Y., Zhu Y., Li N., Zhang N., Feng Z., Niu M. CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity. Biochem Biophys Res Commun. 2018 Nov 2;505(3):865-871. doi: 10.1016/j.bbrc.2018.09.182.

33. Chao G., Li X., Ji Y., Zhu Y., Li N., Zhang N., Feng Z., Niu M. MiR-155 controls follicular Treg cell-mediated humoral autoimmune intestinal injury by inhibiting CTLA-4 expression.Int Immunopharmacol. 2019 Jun;71:267-276. doi: 10.1016/j.intimp.2019.03.009.

34. Schneider M.A., Meingassner J. G., Lipp M., Moore H. D., Rot A. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med. 2007 Apr 16;204(4):735-45. doi: 10.1084/jem.20061405.

35. Takagi S., Kinouchi Y., Chida M., Hiwatashi N., Noguchi M., Takahashi S., Shimosegawa T. Strong telomerase activity of B lymphocyte from mesenteric lymph nodes of patients with inflammatory bowel disease. Dig Dis Sci. 2003 Oct;48(10):2091-4. doi: 10.1023/a:1026107429546.

36. Tabibian-Keissar H., Zuckerman N. S., Barak M. et al. B-cell clonal diversification and gut-lymph node trafficking in ulcerative colitis revealed using lineage tree analysis. Eur J Immunol. 2008 Sep;38(9):2600-9. doi: 10.1002/eji.200838333.

37. Mizoguchi E., Mizoguchi A., Chiba C., Niles J. L., Bhan A. K. Antineutrophil cytoplasmic antibodies in T-cell receptor alpha-deficient mice with chronic colitis. Gastroenterology. 1997 Dec;113(6):1828-35. doi: 10.1016/s0016-5085(97)70002-7.

38. Chassaing B., Etienne-Mesmin L., Bonnet R., Darfeuille-Michaud A. Bile salts induce long polar fimbriae expression favouring Crohn’s disease-associated adherent-invasive Escherichia coli interaction with Peyer’s patches. Environ Microbiol. 2013 Feb;15(2):355-71. doi: 10.1111/j.1462-2920.2012.02824.x.

39. Larabi A., Salesse L., Cordonnier C., Etienne-Mesmin L., Barnich N., Dalmasso G., Nguyen H. T.T. Differential miRNA-Gene Expression in M Cells in Response to Crohn’s Disease-Associated AIEC. Microorganisms. 2020 Aug 7;8(8):1205. doi: 10.3390/microorganisms8081205.

40. Vazeille E., Chassaing B., Buisson A. et al. GipA Factor Supports Colonization of Peyer’s Patches by Crohn’s Disease-associated Escherichia Coli. Inflamm Bowel Dis. 2016 Jan;22(1):68-81. doi: 10.1097/MIB.0000000000000609.

41. Pararasa C., Zhang N., Tull T. J. et al. Reduced CD27-IgD- B Cells in Blood and Raised CD27-IgD- B Cells in Gut-Associated Lymphoid Tissue in Inflammatory Bowel Disease. Front Immunol. 2019 Mar 5;10:361. doi: 10.3389/fimmu.2019.00361.

42. Qian T., Hong J., Wang L., Wang Z., Lu Z., Li Y., Liu R., Chu Y. Regulation of CD11b by HIF-1α and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease. Mol Immunol. 2019 Jul;111:162-171. doi: 10.1016/j.molimm.2019.04.005.

43. Watabe T., Nagaishi T., Tsugawa N. et al. B cell activation in the cecal patches during the development of an experimental colitis model. Biochem Biophys Res Commun. 2018 Feb 5;496(2):367-373. doi: 10.1016/j.bbrc.2018.01.053.

44. Gardenbroek T.J., Pinkney T. D., Sahami S., Morton D. G. et al. The ACCURE-trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicenter trial (NTR2883) and the ACCURE-UK trial: a randomised external pilot trial (ISRCTN56523019). BMC Surg. 2015 Mar 18;15:30. doi: 10.1186/s12893-015-0017-1.

45. Vignali D.A., Kuchroo V. K. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012 Jul 19;13(8):722-8. doi: 10.1038/ni.2366.

46. Kaliński P., Hilkens C. M., Snijders A., Snijdewint F. G., Kapsenberg M. L. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol. 1997 Jul 1;159(1):28-35. PMID: 9200435.

47. Oppmann B., Lesley R., Blom B., Timans J. C. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25. doi: 10.1016/s1074-7613(00)00070-4.

48. Korta A., Kula J., Gomułka K. The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease.Int J Mol Sci. 2023 Jun 15;24(12):10172. doi: 10.3390/ijms241210172.

49. Tang C., Chen S., Qian H., Huang W.Interleukin-23: as a drug target for autoimmune inflammatory diseases. Immunology. 2012 Feb;135(2):112-24. doi: 10.1111/j.1365-2567.2011.03522.x.

50. Li Y., Wang H., Lu H., Hua S. Regulation of Memory T Cells by Interleukin-23.Int Arch Allergy Immunol. 2016;169(3):157-62. doi: 10.1159/000445834.

51. Langowski J.L., Zhang X., Wu L., Mattson J. D., Chen T., Smith K., Basham B., McClanahan T., Kastelein R. A., Oft M. IL-23 promotes tumour incidence and growth. Nature. 2006 Jul 27;442(7101):461-5. doi: 10.1038/nature04808.

52. Yi Dong, Blake Johnson, Ian Chiu, Tatianna Larman, Rong Li; Investigating the Interaction of Inflammation-Associated Fibroblasts (IAFs) with Colon Epithelial Cells in Inflammatory Bowel Disease (IBD). J Immunol. 2023; 210 (1_Supplement): 61.03. doi: 10.4049/jimmunol.210.Supp.61.03.

53. Researchers discover a possible cause of chronic inflammations of Crohn Disease”. Genomics & Genetics Weekly: 72. August 11, 2006.

54. Wehkamp J., Salzman N. H., Porter E., Nuding S. et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34. doi: 10.1073/pnas.0505256102.

55. Dudakov J.A., Hanash A. M., van den Brink M. R.Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015;33:747-85. doi: 10.1146/annurev-immunol-032414-112123.

56. Lal S., Kandiyal B., Ahuja V., Takeda K., Das B. Gut microbiome dysbiosis in inflammatory bowel disease. Prog Mol Biol Transl Sci. 2022;192(1):179-204. doi: 10.1016/bs.pmbts.2022.09.003.

57. Otte J.M., Vordenbäumen S. Role of Antimicrobial Peptides in Inflammatory Bowel Dis-ease. Polymers. 2011;(3):2010-2017. doi: 10.3390/polym3042010.

58. Antoni L., Nuding S., Wehkamp J., Stange E. F.Intestinal barrier in inflammatory bowel disease. World J Gastroenterol. 2014 Feb 7;20(5):1165-79. doi: 10.3748/wjg.v20.i5.1165.

59. Velikova T. Immunological aspects of inflammatory bowel disease pathogenesis. Gastroenterol Hepatol Endosc. 2018;3(4):1-3. doi: 10.15761/GHE.1000171.

60. Ayabe T., Satchell D. P., Wilson C. L., Parks W. C., Selsted M. E., Ouellette A. J. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000 Aug;1(2):113-8. doi: 10.1038/77783.

61. Murphy K., Weaver C. Janeway’s Immunobiology. Garland Science. 2017. 48. ISBN 978-0-8153-4505-3.

62. Luchetti M.M., Ciccia F., Avellini C., Benfaremo D. et al. Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-associated spondyloarthritis. Rheumatology (Oxford). 2021 Jan 5;60(1):92-102. doi: 10.1093/rheumatology/keaa164.

63. Wang J., Chen W. D., Wang Y. D. The Relationship Between Gut Microbiota and Inflammatory Diseases: The Role of Macrophages. Front Microbiol. 2020 Jun 9;11:1065. doi: 10.3389/fmicb.2020.01065.

64. Impellizzeri D., Fusco R., Genovese T., Cordaro M. et al. Coriolus Versicolor Downregulates TLR4/NF-κB Signaling Cascade in Dinitrobenzenesulfonic Acid-Treated Mice: A Possible Mechanism for the Anti-Colitis Effect. Antioxidants (Basel). 2022 Feb 17;11(2):406. doi: 10.3390/antiox11020406.

65. Xia X., Lin H., Luo F., Wu X., Zhu L., Chen S., Luo H., Ye F., Peng X., Zhang Y., Yang G., Lin Q. Oryzanol Ameliorates DSS-Stimulated Gut Barrier Damage via Targeting the Gut Microbiota Accompanied by the TLR4/NF-κB/NLRP3 Cascade Response In Vivo. J Agric Food Chem. 2022 Dec 21;70(50):15747-15762. doi: 10.1021/acs.jafc.2c04354.

66. Pastorelli L., Dozio E., Pisani L. F. et al. Procoagulatory state in inflammatory bowel diseases is promoted by impaired intestinal barrier function. Gastroenterol Res Pract. 2015;2015:189341. doi: 10.1155/2015/189341.

67. Liu S., Zhao W., Lan P., Mou X. The microbiome in inflammatory bowel diseases: from pathogenesis to therapy. Protein Cell. 2021 May;12(5):331-345. doi: 10.1007/s13238-020-00745-3.

68. Basic M., Peppermüller P. P., Bolsega S., Bleich A., Bornemann M., Bode U., Buettner M. Lymph Node Stromal Cells From Different Draining Areas Distinctly Regulate the Development of Chronic Intestinal Inflammation. Front Immunol. 2021 Feb 16;11:549473. doi: 10.3389/fimmu.2020.549473.

69. Acedo S.C., Gotardo E. M., Lacerda J. M., de Oliveira C. C., de Oliveira Carvalho P., Gambero A. Perinodal adipose tissue and mesenteric lymph node activation during reactivated TNBS-colitis in rats. Dig Dis Sci. 2011 Sep;56(9):2545-52. doi: 10.1007/s10620-011-1644-8.

70. Schwager S., Detmar M. Inflammation and Lymphatic Function. Front Immunol. 2019 Feb 26;10:308. doi: 10.3389/fimmu.2019.00308.

71. Rehal S., Stephens M., Roizes S., Liao S., von der Weid P. Y. Acute small intestinal inflammation results in persistent lymphatic alterations. Am J Physiol Gastrointest Liver Physiol. 2018 Mar 1;314(3): G408-G417. doi: 10.1152/ajpgi.00340.2017.

72. Rehal S., von der Weid P. Y. Experimental ileitis alters prostaglandin biosynthesis in mesenteric lymphatic and blood vessels. Prostaglandins Other Lipid Mediat. 2015 Jan-Mar;116-117:37-48. doi: 10.1016/j.prostaglandins.2014.11.001.

73. Becker F., Potepalov S., Shehzahdi R. et al. Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function? Inflamm Bowel Dis. 2015 Jun;21(6):1282-96. doi: 10.1097/MIB.0000000000000371.

74. Mathias R., von der Weid P. Y. Involvement of the NO-cGMP-K(ATP) channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis. Am J Physiol Gastrointest Liver Physiol. 2013 Mar 15;304(6): G623-34. doi: 10.1152/ajpgi.00392.2012.

75. Low S., Hirakawa J., Hoshino H., Uchimura K., Kawashima H., Kobayashi M. Role of MAdCAM-1-Expressing High Endothelial Venule-Like Vessels in Colitis Induced in Mice Lacking Sulfotransferases Catalyzing L-Selectin Ligand Biosynthesis. J Histochem Cytochem. 2018 Jun;66(6):415-425. doi: 10.1369/0022155417753363.

76. Rahier J.F., Dubuquoy L., Colombel J. F., Jouret-Mourin A. et al. Decreased lymphatic vessel density is associated with postoperative endoscopic recurrence in Crohn’s disease. Inflamm Bowel Dis. 2013 Sep;19(10):2084-90. doi: 10.1097/MIB.0b013e3182971cec.

77. Shen W., Li Y., Cao L., Cai X., Ge Y., Zhu W. Decreased Expression of Prox1 Is Associated With Postoperative Recurrence in Crohn’s Disease. J Crohns Colitis. 2018 Nov 9;12(10):1210-1218. doi: 10.1093/ecco-jcc/jjy091.

78. Sato H., Higashiyama M., Hozumi H. et al. Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis. Am J Physiol Gastrointest Liver Physiol. 2016 Aug 1;311(2): G276-85. doi: 10.1152/ajpgi.00455.2015.

79. Tacconi C., Schwager S., Cousin N., Bajic D., Sesartic M., Sundberg J. P., Neri D., Detmar M. Antibody-Mediated Delivery of VEGFC Ameliorates Experimental Chronic Colitis. ACS Pharmacol Transl Sci. 2019 Aug 1;2(5):342-352. doi: 10.1021/acsptsci.9b00037.

80. Wang X.L., Zhao J., Qin L., Qiao M. Promoting inflammatory lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) aggravated intestinal inflammation in mice with experimental acute colitis. Braz J Med Biol Res. 2016;49(5): e4738. doi: 10.1590/1414-431X20154738.

81. Bandinelli F., Milia A. F., Manetti M., Lastraioli E., D’Amico M., Tonelli P., Fazi M., Arcangeli A., Matucci-Cerinic M., Ibba-Manneschi L. Lymphatic endothelial progenitor cells and vascular endothelial growth factor-C in spondyloarthritis and Crohn’s disease: two overlapping diseases? Clin Exp Rheumatol. 2015 Mar-Apr;33(2):195-200.

82. D’Alessio S., Tacconi C., Danese S. Targeting lymphatics in inflammatory bowel disease. Oncotarget. 2015 Oct 27;6(33):34047-8. doi: 10.18632/oncotarget.6026.

83. Hosono K., Kojo K., Narumiya S., Majima M., Ito Y. Prostaglandin E receptor EP4 stimulates lymphangiogenesis to promote mucosal healing during DSS-induced colitis. Biomed Pharmacother. 2020 Aug;128:110264. doi: 10.1016/j.biopha.2020.110264.

84. Jurisic G., Sundberg J. P., Detmar M. Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis. 2013 Aug;19(9):1983-9. doi: 10.1097/MIB.0b013e31829292f7.

85. Davis R.B., Kechele D. O., Blakeney E. S., Pawlak J. B., Caron K. M. Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation. JCI Insight. 2017 Mar 23;2(6): e92465. doi: 10.1172/jci.insight.92465.

86. Merga Y., Campbell B. J., Rhodes J. M. Mucosal barrier, bacteria and inflammatory bowel disease: possibilities for therapy. Dig Dis. 2014;32(4):475-83. doi: 10.1159/000358156.

87. Kashirskaya N. Yu., Khavkin A. I. and others. The use of human intestinal organoids in inflammatory bowel diseases: from an experimental model to regenerative therapy. VDD. 2023, Vol.5. (in Russ.)@@ Каширская Н. Ю., Хавкин А. И. и др. Использование кишечных органоидов человека при воспалительных заболеваниях кишечника: от экспериментальной модели к регенеративной терапии. ВДД. 2023, Т. 5.

88. Howell K.J., Kraiczy J., Nayak K. M. et al. DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome. Gastroenterology. 2018 Feb;154(3):585-598. doi: 10.1053/j.gastro.2017.10.007.