New developments in goblet cell mucus secretion and function

Goblet cells and their main secretory product, mucus, have long been poorly appreciated; however, recent discoveries have changed this and placed these cells at the center stage of our understanding of mucosal biology and the immunology of the intestinal tract. The mucus system differs substantially between the small and large intestine, although it is built around MUC2 mucin polymers in both cases. Furthermore, that goblet cells and the regulation of their secretion also differ between these two parts of the intestine is of fundamental importance for a better understanding of mucosal immunology. There are several types of goblet cell that can be delineated based on their location and function. The surface colonic goblet cells secrete continuously to maintain the inner mucus layer, whereas goblet cells of the colonic and small intestinal crypts secrete upon stimulation, for example, after endocytosis or in response to acetyl choline. However, despite much progress in recent years, our understanding of goblet cell function and regulation is still in its infancy.

[1]  D. Ron,et al.  Negative feedback by IRE1β optimizes mucin production in goblet cells , 2013, Proceedings of the National Academy of Sciences.

[2]  B. Stockinger,et al.  IL-22 Mediates Goblet Cell Hyperplasia and Worm Expulsion in Intestinal Helminth Infection , 2013, PLoS pathogens.

[3]  M. Johansson,et al.  Is the intestinal goblet cell a major immune cell? , 2014, Cell host & microbe.

[4]  Susan D. Spencer,et al.  The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor , 1998, The Journal of experimental medicine.

[5]  R. Specian,et al.  Regulation of intestinal goblet cell secretion. II. A survey of potential secretagogues. , 1982, The American journal of physiology.

[6]  A. Hayday,et al.  Epithelial decision makers: in search of the 'epimmunome' , 2010, Nature Immunology.

[7]  G. Radford-Smith,et al.  An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity , 2010, Mucosal Immunology.

[8]  M. Bäckström,et al.  Intestinal MUC2 mucin supramolecular topology by packing and release resting on D3 domain assembly. , 2014, Journal of molecular biology.

[9]  M. Johansson,et al.  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. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[10]  C. Dejong,et al.  Ischaemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon , 2012, Gut.

[11]  M. Johansson,et al.  Keeping Bacteria at a Distance , 2011, Science.

[12]  F. Finkelman,et al.  Interleukin‐4‐ and interleukin‐13‐mediated host protection against intestinal nematode parasites , 2004, Immunological reviews.

[13]  F. Bäckhed,et al.  Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus , 2014, Proceedings of the National Academy of Sciences.

[14]  Jerrold R. Turner,et al.  Intestinal mucosal barrier function in health and disease , 2009, Nature Reviews Immunology.

[15]  M. Johansson,et al.  Fast Renewal of the Distal Colonic Mucus Layers by the Surface Goblet Cells as Measured by In Vivo Labeling of Mucin Glycoproteins , 2012, PloS one.

[16]  D. Hopwood,et al.  Uptake of cationized ferritin by colonic epithelium , 1983, The Journal of pathology.

[17]  C. Goodnow,et al.  Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis , 2008, PLoS medicine.

[18]  R. Sartor,et al.  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[19]  J. Renauld,et al.  IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa 1 , 2009, The Journal of Immunology.

[20]  A. Gewirtz,et al.  Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis , 2013, Gut.

[21]  H. Verspaget,et al.  Infliximab treatment influences the serological expression of matrix metalloproteinase (MMP)‐2 and ‐9 in Crohn's disease , 2007, Inflammatory bowel diseases.

[22]  Y. Kim,et al.  Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. , 1994, The Journal of biological chemistry.

[23]  W. Fiers,et al.  Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. , 2000, Science.

[24]  P. Quinton,et al.  Mucin exocytosis. , 1991, The American review of respiratory disease.

[25]  A. D. Cole THE AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE AND AFFILIATED SOCIETIES SECTION B--PHYSICS. , 1911, Science.

[26]  M. McGuckin,et al.  MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli , 2012, Mucosal Immunology.

[27]  I. Zuna,et al.  In situ expression of interleukin-10 in noninflamed human gut and in inflammatory bowel disease. , 1998, The American journal of pathology.

[28]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[29]  S. Hasnain,et al.  IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells. , 2013, Gastroenterology.

[30]  M. Colonna Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. , 2009, Immunity.

[31]  J. Bouma,et al.  Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice , 2008, Laboratory Investigation.

[32]  W. Ouyang,et al.  Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes , 2014, Nature.

[33]  Hans Clevers,et al.  The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. , 2009, Gastroenterology.

[34]  H. Clevers The Intestinal Crypt, A Prototype Stem Cell Compartment , 2013, Cell.

[35]  Hiroyuki Miyoshi,et al.  Autophagy proteins control goblet cell function by potentiating reactive oxygen species production , 2013, The EMBO journal.

[36]  M. Johansson,et al.  An ex vivo method for studying mucus formation , properties , and thickness in human colonic biopsies and mouse small and large intestinal explants , 2012 .

[37]  R. Ley,et al.  The Antibacterial Lectin RegIIIγ Promotes the Spatial Segregation of Microbiota and Host in the Intestine , 2011, Science.

[38]  H. C. Hartzell,et al.  Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon. , 2010, The Journal of clinical investigation.

[39]  P. Quinton,et al.  Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. , 2009, The Journal of clinical investigation.

[40]  D. Voehringer,et al.  Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths , 2014, Mucosal Immunology.

[41]  R. Kühn,et al.  Interleukin-10 Deficient Mice , 1995 .

[42]  M. Johansson,et al.  Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype , 2012, The Journal of experimental medicine.

[43]  J. Bertin,et al.  A Functional Role for Nlrp6 in Intestinal Inflammation and Tumorigenesis , 2011, The Journal of Immunology.

[44]  Lena Holm,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2010, Gut microbes.

[45]  S. Halm,et al.  Secretagogue response of goblet cells and columnar cells in human colonic crypts. , 1999, American journal of physiology. Cell physiology.

[46]  R. Specian,et al.  Regulation of intestinal goblet cell secretion. I. Role of parasympathetic stimulation. , 1982, The American journal of physiology.

[47]  J. Whitehead,et al.  Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress , 2014, Nature Medicine.

[48]  Y. Belkaid,et al.  Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection , 2013, Nature Medicine.

[49]  Lawrence A Tabak,et al.  Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. , 2012, Glycobiology.

[50]  D. Strachan,et al.  Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility , 2008, Nature Genetics.

[51]  F. Brombacher,et al.  IL-4/IL-13 independent goblet cell hyperplasia in experimental helminth infections , 2008, BMC Immunology.

[52]  Philip Sutton,et al.  Mucin dynamics and enteric pathogens , 2011, Nature Reviews Microbiology.

[53]  W. Hardt,et al.  Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. , 2014, Cell host & microbe.

[54]  B. Johansson,et al.  Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin , 2012, Proceedings of the National Academy of Sciences.

[55]  Vishva M. Dixit,et al.  Mechanisms and Functions of Inflammasomes , 2014, Cell.

[56]  C. Hetz The unfolded protein response: controlling cell fate decisions under ER stress and beyond , 2012, Nature Reviews Molecular Cell Biology.

[57]  H. Harmsen,et al.  The interaction between the mucosal immune system and the commensal microflora of the , 2018 .

[58]  D. Ron,et al.  The ER stress transducer IRE1β is required for airway epithelial mucin production , 2012, Mucosal Immunology.

[59]  R. Newberry,et al.  Microbial Sensing by Goblet Cells Controls Immune Surveillance of Luminal Antigens in the Colon , 2014, Mucosal Immunology.

[60]  V. Herzog Pathways of endocytosis in secretory cells , 1981 .

[61]  Susan E Wert,et al.  SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. , 2009, The Journal of clinical investigation.

[62]  T. Karlsen,et al.  Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis , 2008, Nature Genetics.

[63]  H. Virgin,et al.  Autophagy in immunity and inflammation , 2011, Nature.

[64]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[65]  Christopher S. Law,et al.  Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents. , 2009, The Journal of clinical investigation.

[66]  M. Vaneechoutte,et al.  Viscosity gradient within the mucus layer determines the mucosal barrier function and the spatial organization of the intestinal microbiota , 2007, Inflammatory bowel diseases.

[67]  R. Specian,et al.  Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine , 1980, The Journal of cell biology.

[68]  R. Specian,et al.  Endocytosis and vesicular traffic in fetal and adult colonic goblet cells , 1987, The Anatomical record.

[69]  H. Clevers,et al.  Paneth cells: maestros of the small intestinal crypts. , 2013, Annual review of physiology.

[70]  E. Elinav,et al.  NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus Secretion , 2014, Cell.

[71]  Rodney D. Newberry,et al.  Goblet cells deliver luminal antigen to CD103+ DCs in the small intestine , 2012, Nature.

[72]  D. Erwin,et al.  The Cambrian Explosion: The Construction of Animal Biodiversity. , 2013 .

[73]  T. Samuelsson,et al.  Gel-forming mucins appeared early in metazoan evolution , 2007, Proceedings of the National Academy of Sciences.

[74]  F. Bäckhed,et al.  The composition of the gut microbiota shapes the colon mucus barrier , 2014, EMBO reports.

[75]  J. Whitsett,et al.  Respiratory epithelial cells orchestrate pulmonary innate immunity , 2014, Nature Immunology.

[76]  B. Malissen,et al.  Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors , 2012, Mucosal Immunology.

[77]  M. Denis,et al.  Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants. , 2008, The Journal of clinical investigation.

[78]  J. Whitsett,et al.  Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation. , 2015, The Journal of clinical investigation.

[79]  K. Adler,et al.  Regulated Mucin Secretion from Airway Epithelial Cells , 2013, Front. Endocrinol..

[80]  N. Barker Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration , 2013, Nature Reviews Molecular Cell Biology.

[81]  F. Rieux-Laucat,et al.  Defective IL10 Signaling Defining a Subgroup of Patients With Inflammatory Bowel Disease , 2011, The American Journal of Gastroenterology.

[82]  Kyle N. Plunkett,et al.  The Uptake of Soluble and Particulate Antigens by Epithelial Cells in the Mouse Small Intestine , 2014, PloS one.