Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype

Gustafsson, Jenny; Ermund, Anna; Ambort, Daniel; Johansson, Malin; Nilsson, Hans C.; Thorell, Kaisa; Hebert, Hans; Sjövall, Henrik; Hansson, Gunnar C.

doi:10.1084/jem.20120562

Cited by 299 publications

(385 citation statements)

References 40 publications

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“…This storage mechanism allows for the release of fully synthesized MUC2 polymers which undergo rapid hydration and expansion on the intestinal epithelial surface to maintain mucus barrier integrity during homeostasis or barrier breach 39. Hydration and expansion of MUC2 polymers is dictated by the ionic composition and water availability at the intestinal epithelial surface, and after secretion, mucin polymers can expand their volume up to 1000 times, becoming entangled within one another to form the structural framework of the mucus gel 39, 40…”

Section: Muc2 Biosynthesismentioning

confidence: 99%

A sticky end for gastrointestinal helminths; the role of the mucus barrier

Sharpe

Thornton

Grencis

2018

Parasite Immunology

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SummaryGastrointestinal (GI) nematodes are a group of successful multicellular parasites that have evolved to coexist within the intestinal niche of multiple species. It is estimated that over 10% of the world's population are chronically infected by GI nematodes, making this group of parasitic nematodes a major burden to global health. Despite the large number of affected individuals, there are few effective treatments to eradicate these infections. Research into GI nematode infections has primarily focused on defining the immunological and pathological consequences on host protection. One important but neglected aspect of host protection is mucus, and the concept that mucus is just a simple barrier is no longer tenable. In fact, mucus is a highly regulated and dynamic‐secreted matrix, underpinned by a physical hydrated network of highly glycosylated mucins, which is increasingly recognized to have a key protective role against GI nematode infections. Unravelling the complex interplay between mucins, the underlying epithelium and immune cells during infection are a major challenge and are required to fully define the protective role of the mucus barrier. This review summarizes the current state of knowledge on mucins and the mucus barrier during GI nematode infections, with particular focus on murine models of infection.

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Section: Muc2 Biosynthesismentioning

confidence: 99%

A sticky end for gastrointestinal helminths; the role of the mucus barrier

Sharpe

Thornton

Grencis

2018

Parasite Immunology

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“…Although a majority of the clinical CF symptoms can be attributed to stagnant mucus, the more precise link between the lack of CFTR function and mucus properties has been difficult to understand. We recently showed that the small intestinal mucus of CF mice, in contrast to the WT, was attached to the epithelium and impossible to aspirate (14). Although CF mice have only minor lung problems, their intestinal phenotype is similar to the human disease characterized by meconium ileus and distal intestinal obstruction syndrome (DIOS).…”

Section: Significancementioning

confidence: 99%

“…Mucins are densely packed in the goblet cell granulae due to Ca 2+ ions and low pH, and the role of bicarbonate is to remove the Ca 2+ ions and increase the pH to allow for the >1,000-fold mucin expansion (4). When already formed mucus was treated with bicarbonate, the mucus was normalized and possible to aspirate, although its increased mucin density remained largely unaltered (14). This suggested that mucin attachment and expansion might be different phenomena and made us analyze this further.…”

Section: Significancementioning

confidence: 99%

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Schutte¹,

Ermund²,

Becker‐Pauly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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165

164

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The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a twolayered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin β was added to the attached mucus of meprin β-deficient mice, the mucus was detached from the epithelium. Similar to meprin β-deficient mice, germ-free mice have attached mucus as they did not shed the membraneanchored meprin β into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin β to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin β cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin β in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.protease | von Willebrand factor | gastrointestinal tract

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“…We speculate that the role of CHE cells is to liquefy lumen content and thus assist in mucus clearance. The proximal jejunum, where CHE cells are most abundant, possesses a particularly low luminal pH that can promote accumulation of firm adherent mucus on epithelial surfaces and intervillus spaces (18,24,28). Indeed, CFTR abundance in CHE cells increases as the cells migrate toward the villus tip, suggesting that the most robust secretion emanates from CHE cells in the villus region.…”

Section: G462mentioning

confidence: 99%

Characterization of CFTR High Expresser cells in the intestine

Jakab¹,

Collaco²,

Ameen

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The CFTR High Expresser (CHE) cells express eightfold higher levels of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel compared with neighboring enterocytes and were first identified by our laboratory (Ameen et al., Gastroenterology 108: 1016, 1995). We used double-label immunofluorescence microscopy to further study these enigmatic epithelial cells in rat intestine in vivo or ex vivo. CHE cells were found in duodenum, most frequent in proximal jejunum, and absent in ileum and colon. CFTR abundance increased in CHE cells along the crypt-villus axis. The basolateral Na+K+Cl− cotransporter NKCC1, a key transporter involved in Cl− secretion, was detected at similar levels in CHE cells and neighboring enterocytes at steady state. Microvilli appeared shorter in CHE cells, with low levels of Myosin 1a, a villus enterocyte-specific motor that retains sucrase/isomaltase in the brush-border membrane (BBM). CHE cells lacked alkaline phosphatase and absorptive villus enterocyte BBM proteins, including Na+H+ exchanger NHE3, Cl−/HCO3− exchanger SLC26A6 (putative anion exchanger 1), and sucrase/isomaltase. High levels of the vacuolar-ATPase proton pump were observed in the apical domain of CHE cells. Levels of the NHE regulatory factor NHERF1, Na-K-ATPase, and Syntaxin 3 were similar to that of neighboring enterocytes. cAMP or acetylcholine stimulation robustly increased apical CFTR and basolateral NKCC1 disproportionately in CHE cells relative to neighboring enterocytes. These data strongly argue for a specialized role of CHE cells in Cl−-mediated “high-volume” fluid secretion on the villi of the proximal small intestine.

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Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype

Abstract: Ileal mucus in CftrΔ508 mice is more adherent, denser, and less penetrable than that of WT mice, but addition of bicarbonate normalizes the properties of CftrΔ508 mucus.

Cited by 299 publications

References 40 publications

A sticky end for gastrointestinal helminths; the role of the mucus barrier

A sticky end for gastrointestinal helminths; the role of the mucus barrier

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Characterization of CFTR High Expresser cells in the intestine

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