The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion

Ståhl, Martin; Tremblay, Sarah; Montero, Marinieve; Vogl, Wayne; Xia, Lijun; Jacobson, Kevan; Menéndez, Alfredo

doi:10.1152/ajpgi.00264.2017

Cited by 21 publications

(12 citation statements)

References 30 publications

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“…Previous studies have identified this electron-lucent halo in murine Paneth cells as predominantly containing Mucin2. 28 Phb1 iΔIEC mice exhibited decreased mRNA expression of antimicrobials produced by Paneth cells such as RegIIIγ , Cryptdin3 , Cryptdin5 and Ang4 ( online supplementary figure S9A ), suggesting loss of Paneth cell function vs simply degranulation of Paneth cell enzymes on a sustained basis.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

Jackson

Panopoulos

Neumann³

et al. 2020

Gut

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ObjectiveAlthough perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD.DesignMale and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice.ResultsPhb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo.ConclusionOur results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

Jackson

Panopoulos

Neumann³

et al. 2020

Gut

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“…Crypt base columnar cells are active stem cells that express olfactomedin 4 ( Olfm4 ), whereas Paneth cells do not express Olfm4 and secrete lysozyme, antimicrobials, and factors that maintain the stem cell niche ( van Es and Cleavers, 2014 ). In mice but not humans, Paneth cells also expressed Muc2 ( Stahl et al., 2018 ). The presence of Paneth cells in the intestinal crypts of chickens is controversial.…”

Section: Discussionmentioning

confidence: 99%

Changes with age in density of goblet cells in the small intestine of broiler chicks

2020

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Goblet cells secrete mucin 2 ( Muc2 ), which is a major component of the mucus that lines the intestinal tract and creates a protective barrier between pathogens and the intestinal epithelial cells and thus are important for chick health. The objectives of this study were to determine the age-specific and intestinal segment–specific expression of Muc2 mRNA and changes in the number of goblet cells from late embryogenesis to early after hatch. Small intestinal samples from the duodenum, jejunum, and ileum were collected from Cobb 500 broilers at embryonic day 19 (e19), day of hatch ( doh ), and day 2 and 4 after hatch. Cells expressing Muc2 mRNA and mucin glycoprotein were detected by in situ hybridization or alcian blue and periodic acid–Schiff staining, respectively. Along the villi, there were many more cells expressing Muc2 mRNA than those stained for mucin glycoprotein. In the crypt, cells expressing Muc2 mRNA did not stain for mucin glycoprotein. There was an increase in the density of goblet cells in the villi and Muc2 mRNA expressing cells in the crypts of the jejunum and ileum from e19 to doh and day 2 to day 4, with no change between doh and day 2. In contrast, in the duodenum, the density of goblet cells in the villi and Muc2 mRNA expressing cells in the crypts remained constant from e19 to day 4. At day 4, the villi in the ileum had a greater density of goblet cells than the duodenum. In the crypt, the ileum had a greater density of Muc2 mRNA expressing cells than the duodenum at doh, and the ileum and jejunum both had greater densities of Muc2 mRNA expressing cells than the duodenum at day 4. These results indicate that the population of goblet cells has reached a steady state by doh in the duodenum, whereas in the jejunum and ileum, a steady-state population was not reached until after hatch.

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“…More tuft and goblet cells in Lyz1 À/À ileum were validated by staining and increased transcripts of Klf4 and Spdef for goblet cells (Figure 2H) (Gregorieff et al, 2009;Katz et al, 2002) and Il25 and Pou2f3 for tuft cells (Figure 2I) (Gerbe et al, 2016;von Moltke et al, 2016). A pronounced goblet cell hyperplasia in the Lyz1 À/À ileum was accompanied by abnormally smaller Paneth cell electron-dense granules surrounded by expanded electron-lucent halos formed by packaging of Muc2 mucin (compare Lyz1 À/À in Figures 2K to WT in 2J and Figures S2C and S2D) (Stahl et al, 2018).…”

Section: Lyz1-deficient Intestines Had Increased Population Of Goblet and Tuft Cellsmentioning

confidence: 91%

Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine

et al. 2020

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Paneth cells are the primary source of C-type lysozyme, a b-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1 À/À hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti-and pro-inflammatory responses, with implications for IBD.

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The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion

Cited by 21 publications

References 30 publications

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

Changes with age in density of goblet cells in the small intestine of broiler chicks

Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine

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