1932
0

Annual Review of Immunology

Volume 43, 2025

Immune Regulation of Goblet Cell and Mucus Functions in Health and Disease

  • Jenny K. Gustafsson1 and Gunnar C. Hansson2
  • 1Department of Physiology, University of Gothenburg, Gothenburg, Sweden; email: [email protected] 2Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden; email: [email protected]
  • Vol. 43:169-189 (Volume publication date April 2025)
  • First published as a Review in Advance on January 03, 2025
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The mucosal surfaces of the body are the most vulnerable points for infection because they are lined by single or multiple layers of very active epithelial cells. The main protector of these cells is the mucus system generated by the specialized goblet cell secreting its main components, the gel-forming mucins. The organization of the mucus varies from an attached mucus that is impenetrable to bacteria in the large intestine to a nonattached, more penetrable mucus in the small intestine. The respiratory tract mucus system clears particles and microorganisms from healthy lungs but causes disease if reorganized to an attached mucus that cannot be efficiently transported. Similarly, transformation of large intestine mucus from impenetrable to penetrable causes chronic inflammation directed toward the intestinal microbiota. Mucus-producing goblet cells are regulated by and responsive to signals from immune cells, and at the same time signal back to the immune system. In this review we focus on the relationship of immune cells with intestinal goblet cells and mucus, making parallels to the respiratory tract.

Keyword(s): colitis, intestine, mucin, mucus, O-glycan, respiratory tract
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-101721-065224
2025-04-25
2025-06-14
Loading full text...

Full text loading...

/deliver/fulltext/immunol/43/1/annurev-immunol-101721-065224.html?itemId=/content/journals/10.1146/annurev-immunol-101721-065224&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Nyström EEL, Martinez-Abad B, Arike L, Birchenough GMH, Nonnecke EB, et al. 2021.. An intercrypt subpopulation of goblet cells is essential for colonic mucus barrier function. . Science 372::eabb1590
     [Crossref] [Google Scholar]
  2. 2.
    Parikh K, Antanaviciute A, Fawkner-Corbett D, Jagielowicz M, Aulicino A, et al. 2019.. Colonic epithelial cell diversity in health and inflammatory bowel disease. . Nature 567::49–55
     [Crossref] [Google Scholar]
  3. 3.
    Birchenough GMH, Nyström EEL, Johansson MEV, Hansson GC. 2016.. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. . Science 352::1535–42
     [Crossref] [Google Scholar]
  4. 4.
    Johansson MEV, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. 2008.. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. . PNAS 105::15064–69
     [Crossref] [Google Scholar]
  5. 5.
    Ermund A, Schutte A, Johansson MEV, Gustafsson JK, Hansson GC. 2013.. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. . Am. J. Physiol. Gastrointest. Liver Physiol. 305::G341–47
     [Crossref] [Google Scholar]
  6. 6.
    Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, et al. 2012.. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. . J. Exp. Med. 209::1263–72
     [Crossref] [Google Scholar]
  7. 7.
    Bergstrom K, Shan X, Casero D, Batushansky A, Lagishetty V, et al. 2020.. Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota. . Science 370::467–72
     [Crossref] [Google Scholar]
  8. 8.
    Bos MF, Ermund A, Hansson GC, de Graaf J. 2023.. Goblet cell interactions reorient bundled mucus strands for efficient airway clearance. . PNAS Nexus 2::pgad388
     [Crossref] [Google Scholar]
  9. 9.
    Fakih D, Rodriguez-Piñeiro AM, Trillo-Muyo S, Evans CM, Ermund A, Hansson GC. 2020.. Normal murine respiratory tract has its mucus concentrated in clouds based on the Muc5b mucin. . Am. J. Physiol. Lung Cell. Mol. Physiol. 318::L1270–79
     [Crossref] [Google Scholar]
  10. 10.
    Hansson GC. 2020.. Mucins and the microbiome. . Annu. Rev. Biochem. 89::769–93
     [Crossref] [Google Scholar]
  11. 11.
    Luis AS, Hansson GC. 2023.. Intestinal mucus and their glycans: a habitat for thriving microbiota. . Cell Host Microbe 31::1087–100
     [Crossref] [Google Scholar]
  12. 12.
    Javitt G, Khmelnitsky L, Albert L, Bigman LS, Elad N, et al. 2020.. Assembly mechanism of mucin and von Willebrand factor polymers. . Cell 183::717–29.e16
     [Crossref] [Google Scholar]
  13. 13.
    Ambort D, Johansson ME, Gustafsson JK, Nilsson HE, Ermund A, et al. 2012.. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. . PNAS 109::5645–50
     [Crossref] [Google Scholar]
  14. 14.
    Carpenter J, Wang Y, Gupta R, Li Y, Haridass P, et al. 2021.. Assembly and organization of the N-terminal region of mucin MUC5AC: indications for structural and functional distinction from MUC5B. . PNAS 118::e2104490118
     [Crossref] [Google Scholar]
  15. 15.
    Recktenwald CV, Karlsson G, Garcia-Bonete MJ, Katona G, Jensen M, et al. 2024.. The structure of the second CysD domain of MUC2 and role in mucin organization by transglutaminase-based cross-linking. . Cell Rep. 43::114207
     [Crossref] [Google Scholar]
  16. 16.
    Layunta E, Jäverfelt S, Dolan B, Arike L, Pelaseyed T. 2021.. IL-22 promotes the formation of a MUC17 glycocalyx barrier in the postnatal small intestine during weaning. . Cell Rep. 34::108757
     [Crossref] [Google Scholar]
  17. 17.
    Agrawal B, Longenecker BM. 2005.. MUC1 mucin-mediated regulation of human T cells. . Int. Immunol. 17::391–99
     [Crossref] [Google Scholar]
  18. 18.
    van Putten JPM, Strijbis K. 2017.. Transmembrane mucins: signaling receptors at the intersection of inflammation and cancer. . J. Innate Immun. 9::281–99
     [Crossref] [Google Scholar]
  19. 19.
    Pelaseyed T, Hansson GC. 2020.. Membrane mucins of the intestine at a glance. . J. Cell Sci. 133::jcs240929
     [Crossref] [Google Scholar]
  20. 20.
    Noah TK, Donahue B, Shroyer NF. 2011.. Intestinal development and differentiation. . Exp. Cell Res. 317::2702–10
     [Crossref] [Google Scholar]
  21. 21.
    Birchenough GMH, Schroeder BO, Sharba S, Arike L, Recktenwald CV, et al. 2023.. Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection. . Cell Rep. 42::112084
     [Crossref] [Google Scholar]
  22. 22.
    Johansson MEV. 2012.. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. . PLOS ONE 7::e41009
     [Crossref] [Google Scholar]
  23. 23.
    Gustafsson JK, Davis JE, Rappai T, McDonald KG, Kulkarni DH, et al. 2021.. Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis. . eLife 10::e67292
     [Crossref] [Google Scholar]
  24. 24.
    Ljungholm PL, Ermund A, Soderlund Garsveden MM, Pettersson VL, Gustafsson JK. 2024.. The anion exchanger slc26a3 regulates colonic mucus expansion during steady state and in response to prostaglandin E2, while Cftr regulates de novo mucus release in response to carbamylcholine. . Pflugers Arch. 476::1209–19
     [Crossref] [Google Scholar]
  25. 25.
    Dolan B, Ermund A, Martinez-Abad B, Johansson MEV, Hansson GC. 2022.. Clearance of small intestinal crypts involves goblet cell mucus secretion by intracellular granule rupture and enterocyte ion transport. . Sci. Signal. 15::eabl5848
     [Crossref] [Google Scholar]
  26. 26.
    Specian RD, Neutra MR. 1980.. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. . J. Cell Biol. 85::626–40
     [Crossref] [Google Scholar]
  27. 27.
    Johansson MEV, Gustafsson JK, Holmen-Larsson J, Jabbar KS, Xia L, et al. 2014.. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. . Gut 63::281–91
     [Crossref] [Google Scholar]
  28. 28.
    Worbs T, Bode U, Yan S, Hoffmann MW, Hintzen G, et al. 2006.. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. . J. Exp. Med. 203::519–27
     [Crossref] [Google Scholar]
  29. 29.
    Kulkarni DH, Gustafsson JK, Knoop KA, McDonald KG, Bidani SS, et al. 2020.. Goblet cell associated antigen passages support the induction and maintenance of oral tolerance. . Mucosal Immunol. 13::271–82
     [Crossref] [Google Scholar]
  30. 30.
    Knoop KA, Gustafsson JK, McDonald KG, Kulkarni DH, Coughlin PE, et al. 2017.. Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. . Sci. Immunol. 2::eaao1314
     [Crossref] [Google Scholar]
  31. 31.
    McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, et al. 2012.. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. . Nature 483::345–49
     [Crossref] [Google Scholar]
  32. 32.
    Knoop KA, Gustafsson JK, McDonald KG, Kulkarni DH, Kassel R, Newberry RD. 2017.. Antibiotics promote the sampling of luminal antigens and bacteria via colonic goblet cell associated antigen passages. . Gut Microbes 8::400–11
     [Crossref] [Google Scholar]
  33. 33.
    Knoop KA, Coughlin PE, Floyd AN, Ndao IM, Hall-Moore C, et al. 2020.. Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis. . PNAS 117::7941–49
     [Crossref] [Google Scholar]
  34. 34.
    Kulkarni DH, McDonald KG, Knoop KA, Gustafsson JK, Kozlowski KM, et al. 2018.. Goblet cell associated antigen passages are inhibited during Salmonella typhimurium infection to prevent pathogen dissemination and limit responses to dietary antigens. . Mucosal Immunol. 11::1103–13
     [Crossref] [Google Scholar]
  35. 35.
    Hill CA, Casterline BW, Valguarnera E, Hecht AL, Shepherd ES, et al. 2024.. Bacteroides fragilis toxin expression enables lamina propria niche acquisition in the developing mouse gut. . Nat. Microbiol. 9::85–94
     [Crossref] [Google Scholar]
  36. 36.
    Sharpe C, Thornton DJ, Grencis RK. 2018.. A sticky end for gastrointestinal helminths; the role of the mucus barrier. . Parasite Immunol. 40::e12517
     [Crossref] [Google Scholar]
  37. 37.
    Tabula Muris Consort. 2018.. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. . Nature 562::367–72
     [Crossref] [Google Scholar]
  38. 38.
    Jones RC, Karkanias J, Krasnow MA, Pisco AO, Quake SR, et al. 2022.. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. . Science 376::eabl4896
     [Crossref] [Google Scholar]
  39. 39.
    Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, et al. 2017.. A single-cell survey of the small intestinal epithelium. . Nature 551::333–39
     [Crossref] [Google Scholar]
  40. 40.
    Gustafsson JK, Linden SK, Alwan AH, Scholte BJ, Hansson GC, Sjovall H. 2015.. Carbachol-induced colonic mucus formation requires transport via NKCC1, K+ channels and CFTR. . Pflugers Arch. 467::1403–15
     [Crossref] [Google Scholar]
  41. 41.
    Garcia MA, Yang N, Quinton PM. 2009.. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion. . J. Clin. Investig. 119::2613–22
     [Crossref] [Google Scholar]
  42. 42.
    Neutra MR, O'Malley LJ, Specian RD. 1982.. Regulation of intestinal goblet cell secretion. II. A survey of potential secretagogues. . Am. J. Physiol. Gastrointest. Liver Physiol. 242::G380–87
     [Crossref] [Google Scholar]
  43. 43.
    Chen EY, Yang N, Quinton PM, Chin WC. 2010.. A new role for bicarbonate in mucus formation. . Am. J. Physiol. Lung Cell. Mol. Physiol. 299::L542–49
     [Crossref] [Google Scholar]
  44. 44.
    Gustafsson JK, Ermund A, Johansson ME, Schutte A, Hansson GC, Sjovall H. 2012.. An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants. . Am. J. Physiol. Gastrointest. Liver Physiol. 302::G430–38
     [Crossref] [Google Scholar]
  45. 45.
    Halm DR, Halm ST. 2000.. Secretagogue response of goblet cells and columnar cells in human colonic crypts. . Am. J. Physiol. Cell Physiol. 278::C212–33
     [Crossref] [Google Scholar]
  46. 46.
    Crowe SE, Luthra GK, Perdue MH. 1997.. Mast cell mediated ion transport in intestine from patients with and without inflammatory bowel disease. . Gut 41::785–92
     [Crossref] [Google Scholar]
  47. 47.
    Sontheimer-Phelps A, Chou DB, Tovaglieri A, Ferrante TC, Duckworth T, et al. 2020.. Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology. . Cell. Mol. Gastroenterol. Hepatol. 9::507–26
     [Crossref] [Google Scholar]
  48. 48.
    Belley A, Chadee K. 1999.. Prostaglandin E2 stimulates rat and human colonic mucin exocytosis via the EP4 receptor. . Gastroenterology 117::1352–62
     [Crossref] [Google Scholar]
  49. 49.
    Ihle JN. 1995.. Cytokine receptor signalling. . Nature 377::591–94
     [Crossref] [Google Scholar]
  50. 50.
    Kang JW, Lee YH, Kang MJ, Lee HJ, Oh R, et al. 2017.. Synergistic mucus secretion by histamine and IL-4 through TMEM16A in airway epithelium. . Am. J. Physiol. Lung Cell. Mol. Physiol. 313::L466–76
     [Crossref] [Google Scholar]
  51. 51.
    Benedetto R, Cabrita I, Schreiber R, Kunzelmann K. 2019.. TMEM16A is indispensable for basal mucus secretion in airways and intestine. . FASEB J. 33::4502–12
     [Crossref] [Google Scholar]
  52. 52.
    Reardon C, Duncan GS, Brüstle A, Brenner D, Tusche MW, et al. 2013.. Lymphocyte-derived ACh regulates local innate but not adaptive immunity. . PNAS 110::1410–15
     [Crossref] [Google Scholar]
  53. 53.
    Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, et al. 2011.. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. . Science 334::98–101
     [Crossref] [Google Scholar]
  54. 54.
    Noah TK, Shroyer NF. 2013.. Notch in the intestine: regulation of homeostasis and pathogenesis. . Annu. Rev. Physiol. 75::263–88
     [Crossref] [Google Scholar]
  55. 55.
    Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. 2001.. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. . Science 294::2155–58
     [Crossref] [Google Scholar]
  56. 56.
    Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, et al. 2000.. Control of endodermal endocrine development by Hes-1. . Nat. Genet. 24::36–44
     [Crossref] [Google Scholar]
  57. 57.
    Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, Zoghbi HY. 2007.. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. . Gastroenterology 132::2478–88
     [Crossref] [Google Scholar]
  58. 58.
    van Es JH, Sato T, van de Wetering M, Lyubimova A, Yee Nee AN, et al. 2012.. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. . Nat. Cell Biol. 14::1099–104
     [Crossref] [Google Scholar]
  59. 59.
    Read E, Peña-Cearra A, Coman D, Jowett GM, Chung MWH, et al. 2024.. Bi-directional signaling between the intestinal epithelium and type-3 innate lymphoid cells regulates secretory dynamics and interleukin-22. . Mucosal Immunol. 17::1–12
     [Crossref] [Google Scholar]
  60. 60.
    Lee JJ, Kim D, Pyo KH, Kim MK, Kim HJ, et al. 2013.. STAT6 expression and IL-13 production in association with goblet cell hyperplasia and worm expulsion of Gymnophalloides seoi from C57BL/6 mice. . Korean J. Parasitol. 51::589–94
     [Crossref] [Google Scholar]
  61. 61.
    Chen S, Zheng Y, Ran X, Du H, Feng H, et al. 2021.. Integrin αEβ7+ T cells direct intestinal stem cell fate decisions via adhesion signaling. . Cell Res. 31::1291–307
     [Crossref] [Google Scholar]
  62. 62.
    Kober OI, Ahl D, Pin C, Holm L, Carding SR, Juge N. 2014.. γδ T-cell-deficient mice show alterations in mucin expression, glycosylation, and goblet cells but maintain an intact mucus layer. . Am. J. Physiol. Gastrointest. Liver Physiol. 306::G582–93
     [Crossref] [Google Scholar]
  63. 63.
    Lindholm HT, Parmar N, Drurey C, Campillo Poveda M, Vornewald PM, et al. 2022.. BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia. . Sci. Immunol. 7::eabl6543
     [Crossref] [Google Scholar]
  64. 64.
    Noah TK, Knoop KA, McDonald KG, Gustafsson JK, Waggoner L, et al. 2019.. IL-13–induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis. . J. Allergy Clin. Immunol. 144::1058–73.e3
     [Crossref] [Google Scholar]
  65. 65.
    Steenwinckel V, Louahed J, Lemaire MM, Sommereyns C, Warnier G, et al. 2009.. IL-9 promotes IL-13-dependent Paneth cell hyperplasia and up-regulation of innate immunity mediators in intestinal mucosa. . J. Immunol. 182::4737–43
     [Crossref] [Google Scholar]
  66. 66.
    Yuan C, Rayasam A, Moe A, Hayward M, Wells C, et al. 2023.. Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling. . Nat. Commun. 14::7963
     [Crossref] [Google Scholar]
  67. 67.
    Waddell A, Vallance JE, Hummel A, Alenghat T, Rosen MJ. 2019.. IL-33 induces murine intestinal goblet cell differentiation indirectly via innate lymphoid cell IL-13 secretion. . J. Immunol. 202::598–607
     [Crossref] [Google Scholar]
  68. 68.
    Fuss IJ, Joshi B, Yang Z, Degheidy H, Fichtner-Feigl S, et al. 2014.. IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. . Gut 63::1728–36
     [Crossref] [Google Scholar]
  69. 69.
    Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K, Hisaeda H, et al. 2017.. Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. . Immunity 46::863–74.e4
     [Crossref] [Google Scholar]
  70. 70.
    Maynard CL, Weaver CT. 2015.. Effector CD4+ T cells in the intestines. . In Mucosal Immunology, ed. J Mestecky, W Strober, MW Russell, BL Kelsall, H Cheroutre, BN Lambrecht , pp. 721–32. Boston:: Academic. , 4th ed..
     [Google Scholar]
  71. 71.
    Mills KHG. 2023.. IL-17 and IL-17-producing cells in protection versus pathology. . Nature Rev. Immunol. 23::38–54
     [Crossref] [Google Scholar]
  72. 72.
    Keir M, Yi Y, Lu T, Ghilardi N. 2020.. The role of IL-22 in intestinal health and disease. . J. Exp. Med. 217::e20192195
     [Crossref] [Google Scholar]
  73. 73.
    Zha J-M, Li H-S, Lin Q, Kuo W-T, Jiang Z-H, et al. 2019.. Interleukin 22 expands transit-amplifying cells while depleting Lgr5+ stem cells via inhibition of Wnt and Notch signaling. . Cell. Mol. Gastroenterol. Hepatol. 7::255–74
     [Crossref] [Google Scholar]
  74. 74.
    Mihi B, Gong Q, Nolan LS, Gale SE, Goree M, et al. 2021.. Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration. . Cell Rep. Med. 2::100320
     [Crossref] [Google Scholar]
  75. 75.
    Turner JE, Stockinger B, Helmby H. 2013.. IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. . PLOS Pathog. 9::e1003698
     [Crossref] [Google Scholar]
  76. 76.
    Bergstrom JH, Birchenough GM, Katona G, Schroeder BO, Schutte A, et al. 2016.. Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG16. . PNAS 113::13833–38
     [Crossref] [Google Scholar]
  77. 77.
    Lee C, Song JH, Cha Y-E, Chang DK, Kim Y-H, Hong SN. 2022.. Intestinal epithelial responses to IL-17 in adult stem cell-derived human intestinal organoids. . J. Crohn's Colitis 16::1911–23
     [Crossref] [Google Scholar]
  78. 78.
    Lin X, Gaudino SJ, Jang KK, Bahadur T, Singh A, et al. 2022.. IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. . Immunity 55::237–53.e8
     [Crossref] [Google Scholar]
  79. 79.
    Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, et al. 1984.. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. . Nature 312::721–24
     [Crossref] [Google Scholar]
  80. 80.
    Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, et al. 1984.. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. . Nature 312::724–29
     [Crossref] [Google Scholar]
  81. 81.
    Perussia B. 1991.. Lymphokine-activated killer cells, natural killer cells and cytokines. . Curr. Opin. Immunol. 3::49–55
     [Crossref] [Google Scholar]
  82. 82.
    Mosmann TR, Coffman RL. 1989.. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. . Annu. Rev. Immunol. 7::145–73
     [Crossref] [Google Scholar]
  83. 83.
    Sad S, Marcotte R, Mosmann TR. 1995.. Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. . Immunity 2::271–79
     [Crossref] [Google Scholar]
  84. 84.
    Reyes EA, Castillo-Azofeifa D, Rispal J, Wald T, Zwick RK, et al. 2023.. Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis. . J. Clin. Investig. 133::e163591
     [Crossref] [Google Scholar]
  85. 85.
    Ninnemann J, Winsauer C, Bondareva M, Kühl AA, Lozza L, et al. 2022.. TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. . Mucosal Immunol. 15::698–716
     [Crossref] [Google Scholar]
  86. 86.
    Van Hauwermeiren F, Vandenbroucke RE, Grine L, Lodens S, Van Wonterghem E, et al. 2015.. TNFR1-induced lethal inflammation is mediated by goblet and Paneth cell dysfunction. . Mucosal Immunol. 8::828–40
     [Crossref] [Google Scholar]
  87. 87.
    Songhet P, Barthel M, Stecher B, Muller AJ, Kremer M, et al. 2011.. Stromal IFN-γR-signaling modulates goblet cell function during Salmonella Typhimurium infection. . PLOS ONE 6::e22459
     [Crossref] [Google Scholar]
  88. 88.
    Morales RA, Rabahi S, Diaz OE, Salloum Y, Kern BC, et al. 2022.. Interleukin-10 regulates goblet cell numbers through Notch signaling in the developing zebrafish intestine. . Mucosal Immunol. 15::940–51
     [Crossref] [Google Scholar]
  89. 89.
    Jenkins BR, Blaseg NA, Grifka-Walk HM, Deuling B, Swain SD, et al. 2021.. Loss of interleukin-10 receptor disrupts intestinal epithelial cell proliferation and skews differentiation towards the goblet cell fate. . FASEB J. 35::e21551
     [Crossref] [Google Scholar]
  90. 90.
    Fu J, Wei B, Wen T, Johansson ME, Liu X, et al. 2011.. Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice. . J. Clin. Investig. 121::1657–66
     [Crossref] [Google Scholar]
  91. 91.
    Bergstrom K, Fu J, Johansson ME, Liu X, Gao N, et al. 2017.. Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. . Mucosal Immunol. 10::91–103
     [Crossref] [Google Scholar]
  92. 92.
    Yao Y, Kim G, Shafer S, Chen Z, Kubo S, et al. 2022.. Mucus sialylation determines intestinal host-commensal homeostasis. . Cell 185::1172–88.e28
     [Crossref] [Google Scholar]
  93. 93.
    Galeev A, Suwandi A, Cepic A, Basu M, Baines JF, Grassl GA. 2021.. The role of the blood group-related glycosyltransferases FUT2 and B4GALNT2 in susceptibility to infectious disease. . Int. J. Med. Microbiol. 311::151487
     [Crossref] [Google Scholar]
  94. 94.
    Bry L, Falk PG, Midtvedt T, Gordon JI. 1996.. A model of host-microbial interactions in an open mammalian ecosystem. . Science 273::1380–83
     [Crossref] [Google Scholar]
  95. 95.
    Holmén Larsson JM, Thomsson KA, Rodriguez-Pineiro AM, Karlsson H, Hansson GC. 2013.. Studies of mucus in mouse stomach, small intestine, and colon. III. Gastrointestinal Muc5ac and Muc2 mucin O-glycan patterns reveal a regiospecific distribution. . Am. J. Physiol. Gastrointest. Liver Physiol. 305::G357–63
     [Crossref] [Google Scholar]
  96. 96.
    Goto Y, Obata T, Kunisawa J, Sato S, Ivanov II, et al. 2014.. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. . Science 345::1254009
     [Crossref] [Google Scholar]
  97. 97.
    Pham TA, Clare S, Goulding D, Arasteh JM, Stares MD, et al. 2014.. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. . Cell Host Microbe 16::504–16
     [Crossref] [Google Scholar]
  98. 98.
    Singh A, Beaupre M, Villegas-Novoa C, Shiomitsu K, Gaudino SJ, et al. 2024.. IL-22 promotes mucin-type O-glycosylation and MATH1+ cell-mediated amelioration of intestinal inflammation. . Cell Rep. 43::114206
     [Crossref] [Google Scholar]
  99. 99.
    Koroleva EP, Fu YX, Tumanov AV. 2018.. Lymphotoxin in physiology of lymphoid tissues – implication for antiviral defense. . Cytokine 101::39–47
     [Crossref] [Google Scholar]
  100. 100.
    Goto Y, Lamichhane A, Kamioka M, Sato S, Honda K, et al. 2015.. IL-10-producing CD4+ T cells negatively regulate fucosylation of epithelial cells in the gut. . Sci. Rep. 5::15918
     [Crossref] [Google Scholar]
  101. 101.
    Hasnain SZ, Dawson PA, Lourie R, Hutson P, Tong H, et al. 2017.. Immune-driven alterations in mucin sulphation is an important mediator of Trichuris muris helminth expulsion. . PLOS Pathog. 13::e1006218
     [Crossref] [Google Scholar]
  102. 102.
    Kotarsky K, Sitnik KM, Stenstad H, Kotarsky H, Schmidtchen A, Koslowski M, et al. 2010.. A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. . Mucosal Immunol. 3::40–48
     [Crossref] [Google Scholar]
  103. 103.
    Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, et al. 2003.. CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer's patch CD11b+ dendritic cells. . J. Immunol. 171::2797–803
     [Crossref] [Google Scholar]
  104. 104.
    Feng X, Ji Y, Zhang C, Jin T, Li J, Guo J. 2023.. CCL6 promotes M2 polarization and inhibits macrophage autophagy by activating PI3-kinase/Akt signalling pathway during skin wound healing. . Exp. Dermatol. 32::403–12
     [Crossref] [Google Scholar]
  105. 105.
    Kunkel EJ, Kim CH, Lazarus NH, Vierra MA, Soler D, et al. 2003.. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. . J. Clin. Investig. 111::1001–10
     [Crossref] [Google Scholar]
  106. 106.
    Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF. 2001.. Regulated MIP-3α/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. . Am. J. Physiol. Gastrointest. Liver Physiol. 280::G710–19
     [Crossref] [Google Scholar]
  107. 107.
    Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, et al. 2000.. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. . J. Exp. Med. 192::761–68
     [Crossref] [Google Scholar]
  108. 108.
    Menten P, Wuyts A, Van Damme J. 2002.. Macrophage inflammatory protein-1. . Cytokine Growth Factor Rev. 13::455–81
     [Crossref] [Google Scholar]
  109. 109.
    Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD. 2002.. IFN-γ-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. . J. Immunol. 168::3195–204
     [Crossref] [Google Scholar]
  110. 110.
    Kulkarni DH, Talati K, Joyce EL, Kousik H, Harris DL, et al. 2024.. Small intestinal goblet cells control humoral immune responses and mobilization during enteric infection. . bioRxiv 2024.01.06.573891. https://doi.org/10.1101/2024.01.06.573891
  111. 111.
    Fahy JV, Dickey BF. 2010.. Airway mucus function and dysfunction. . N. Engl. J. Med. 363::2233–47
     [Crossref] [Google Scholar]
  112. 112.
    Hill DB, Button B, Rubinstein M, Boucher RC. 2022.. Physiology and pathophysiology of human airway mucus. . Physiol. Rev. 102::1757–836
     [Crossref] [Google Scholar]
  113. 113.
    Widdicombe JH, Wine JJ. 2015.. Airway gland structure and function. . Physiol. Rev. 95::1241–319
     [Crossref] [Google Scholar]
  114. 114.
    Ermund A, Meiss LN, Rodriguez-Pineiro AM, Bähr A, Nilsson HE, et al. 2017.. The normal trachea is cleaned by MUC5B mucin bundles from the submucosal glands coated with the MUC5AC mucin. . Biochem. Biophys. Res. Commun. 492::331–37
     [Crossref] [Google Scholar]
  115. 115.
    Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, et al. 2014.. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. . Science 345::818–22
     [Crossref] [Google Scholar]
  116. 116.
    Hoegger MJ, Awadalla M, Namati E, Itani OA, Fischer AJ, et al. 2014.. Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs. . PNAS 111::2355–60
     [Crossref] [Google Scholar]
  117. 117.
    Ermund A, Meiss LN, Dolan B, Jaudas F, Ewaldsson L, et al. 2021.. Mucus threads from surface goblet cells clear particles from the airways. . Respir. Res. 22::303
     [Crossref] [Google Scholar]
  118. 118.
    Okuda K, Chen G, Subramani DB, Wolf M, Gilmore RC, et al. 2019.. Localization of secretory mucins MUC5AC and MUC5B in normal/healthy human airways. . Am. J. Respir. Crit. Care Med. 199::715–27
     [Crossref] [Google Scholar]
  119. 119.
    Ridley C, Thornton DJ. 2018.. Mucins: the frontline defence of the lung. . Biochem. Soc. Trans. 46::1099–106
     [Crossref] [Google Scholar]
  120. 120.
    Chen G, Korfhagen TR, Xu Y, Kitzmiller J, Wert SE, et al. 2009.. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. . J. Clin. Investig. 119::2914–24
     [Crossref] [Google Scholar]
  121. 121.
    Park KS, Korfhagen TR, Bruno MD, Kitzmiller JA, Wan H, et al. 2007.. SPDEF regulates goblet cell hyperplasia in the airway epithelium. . J Clin. Investig. 117::978–88
     [Crossref] [Google Scholar]
  122. 122.
    Chen G, Sun L, Kato T, Okuda K, Martino MB, et al. 2019.. IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis. . J. Clin. Investig. 129::4433–50
     [Crossref] [Google Scholar]
  123. 123.
    Busse PJ, Zhang TF, Srivastava K, Lin BP, Schofield B, et al. 2005.. Chronic exposure to TNF-α increases airway mucus gene expression in vivo. . J. Allergy Clin. Immunol. 116::1256–63
     [Crossref] [Google Scholar]
  124. 124.
    Takeyama K, Fahy JV, Nadel JA. 2001.. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. . Am. J. Respir. Crit. Care Med. 163::511–16
     [Crossref] [Google Scholar]
  125. 125.
    Mitchell C, Provost K, Niu N, Homer R, Cohn L. 2011.. IFN-γ acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease. . J. Immunol. 187::3815–20
     [Crossref] [Google Scholar]
  126. 126.
    Cohn L, Homer RJ, Niu N, Bottomly K. 1999.. T helper 1 cells and interferon γ regulate allergic airway inflammation and mucus production. . J. Exp. Med. 190::1309–18
     [Crossref] [Google Scholar]
  127. 127.
    Rajavelu P, Chen G, Xu Y, Kitzmiller JA, Korfhagen TR, Whitsett JA. 2015.. Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation. . J. Clin. Investig. 125::2021–31
     [Crossref] [Google Scholar]
  128. 128.
    van der Post S, Jabbar KS, Birchenough G, Arike L, Akhtar N, et al. 2019.. Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis. . Gut 68::2142–51
     [Crossref] [Google Scholar]
  129. 129.
    McCormick DA, Horton LW, Mee AS. 1990.. Mucin depletion in inflammatory bowel disease. . J. Clin. Pathol. 43::143–46
     [Crossref] [Google Scholar]
  130. 130.
    Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, et al. 2006.. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. . Gastroenterology 131::117–29
     [Crossref] [Google Scholar]
  131. 131.
    Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, et al. 2002.. Colorectal cancer in mice genetically deficient in the mucin Muc2. . Science 295::1726–29
     [Crossref] [Google Scholar]
  132. 132.
    Johansson ME, Gustafsson JK, Sjoberg KE, Petersson J, Holm L, et al. 2010.. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. . PLOS ONE 5::e12238
     [Crossref] [Google Scholar]
  133. 133.
    Gallego P, Garcia-Bonete M-J, Trillo-Muyo S, Recktenwald CV, Johansson ME, Hansson GC. 2023.. The intestinal MUC2 mucin C-terminus is stabilized by an extra disulfide bond in comparison to von Willebrand factor and other gel-forming mucins. . Nat. Commun. 14::1969
     [Crossref] [Google Scholar]
  134. 134.
    Sharpen JDA, Dolan B, Nyström EEL, Birchenough GMH, Arike L, et al. 2022.. Transglutaminase 3 crosslinks the secreted gel-forming mucus component Mucin-2 and stabilizes the colonic mucus layer. . Nat. Commun. 13::45
     [Crossref] [Google Scholar]
  135. 135.
    Grey MJ, De Luca H, Ward DV, Kreulen IA, Bugda Gwilt K, et al. 2022.. The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development. . J. Clin. Investig. 132::e153519
     [Crossref] [Google Scholar]
  136. 136.
    Singh V, Johnson K, Yin J, Lee S, Lin R, et al. 2022.. Chronic inflammation in ulcerative colitis causes long-term changes in goblet cell function. . Cell. Mol. Gastroenterol. Hepatol. 13::219–32
     [Crossref] [Google Scholar]
  137. 137.
    Ohman L, Dahlén R, Isaksson S, Sjöling A, Wick MJ, et al. 2013.. Serum IL-17A in newly diagnosed treatment-naive patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease. . Inflamm. Bowel Dis. 19::2433–39
     [Crossref] [Google Scholar]
  138. 138.
    Penrose HM, Iftikhar R, Collins ME, Toraih E, Ruiz E, et al. 2021.. Ulcerative colitis immune cell landscapes and differentially expressed gene signatures determine novel regulators and predict clinical response to biologic therapy. . Sci. Rep. 11::9010
     [Crossref] [Google Scholar]
  139. 139.
    Sandborn WJ, Rutgeerts P, Feagan BG, Reinisch W, Olson A, et al. 2009.. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. . Gastroenterology 137::1250–60
     [Crossref] [Google Scholar]
  140. 140.
    Sandborn WJ, Lawendy N, Danese S, Su C, Loftus EV Jr., et al. 2022.. Safety and efficacy of tofacitinib for treatment of ulcerative colitis: final analysis of OCTAVE Open, an open-label, long-term extension study with up to 7.0 years of treatment. . Aliment. Pharmacol. Ther. 55::464–78
     [Crossref] [Google Scholar]
  141. 141.
    Boucher RC. 2019.. Muco-obstructive lung diseases. . N. Engl. J. Med. 380::194153
     [Crossref] [Google Scholar]
  142. 142.
    Radicioni G, Ceppe A, Ford AA, Alexis NE, Barr RG, et al. 2021.. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. . Lancet Respir. Med. 9::1241–54
     [Crossref] [Google Scholar]
  143. 143.
    Hoang ON, Ermund A, Jaramillo AM, Fakih D, French CB, et al. 2022.. Mucins MUC5AC and MUC5B are variably packaged in the same and in separate secretory granules. . Am. J. Respir. Crit. Care Med. 206::1081–95
     [Crossref] [Google Scholar]
  144. 144.
    Fernández-Blanco JA, Fakih D, Arike L, Rodriguez-Pineiro AM, Martinez-Abad B, et al. 2018.. Attached stratified mucus separates bacteria from the epithelial cells in COPD lungs. . JCI. Insight 3::e120994
     [Crossref] [Google Scholar]
  145. 145.
    Stoltz DA, Meyerholz DK, Welsh MJ. 2015.. Origins of cystic fibrosis lung disease. . N. Engl. J. Med. 372::351–62
     [Crossref] [Google Scholar]
  146. 146.
    Quinton PM. 2008.. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. . Lancet 372::415–17
     [Crossref] [Google Scholar]
  147. 147.
    Burgel PR, Montani D, Danel C, Dusser DJ, Nadel JA. 2007.. A morphometric study of mucins and small airway plugging in cystic fibrosis. . Thorax 62::153–61
     [Crossref] [Google Scholar]
  148. 148.
    Fahy JV. 2015.. Type 2 inflammation in asthma—present in most, absent in many. . Nat. Rev. Immunol. 15::57–65
     [Crossref] [Google Scholar]
  149. 149.
    Tanabe T, Rubin BK. 2016.. Airway goblet cells secrete pro-inflammatory cytokines, chemokines, and growth factors. . Chest 149::714–20
     [Crossref] [Google Scholar]
  150. 150.
    Lange P, Halpin DM, O'Donnell DE, MacNee W. 2016.. Diagnosis, assessment, and phenotyping of COPD: beyond FEV1. . Int. J. Chronic Obstr. Pulm. Dis. 11:(Special Issue):3–12
     [Google Scholar]
/content/journals/10.1146/annurev-immunol-101721-065224
Loading
Immune Regulation of Goblet Cell and Mucus Functions in Health and Disease
Annual Review of Immunology 43, 169 (2025); https://doi.org/10.1146/annurev-immunol-101721-065224
/content/journals/10.1146/annurev-immunol-101721-065224
/content/journals/10.1146/annurev-immunol-101721-065224
Loading

Data & Media loading...

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error