| 1. |
- Birchenough, George M. H., et al.
(författare)
-
New developments in goblet cell mucus secretion and function
- 2015
-
Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:4, s. 712-719
-
Forskningsöversikt (refereegranskat)abstract
- 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.
|
|
| 2. |
- Pelaseyed, Thaher, 1979, et al.
(författare)
-
The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system
- 2014
-
Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 260:1, s. 8-20
-
Forskningsöversikt (refereegranskat)abstract
- The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
|
|
| 3. |
- Bergström, Joakim H., 1977, et al.
(författare)
-
AGR2, an endoplasmic reticulum protein, is secreted into the gastrointestinal mucus.
- 2014
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- The MUC2 mucin is the major constituent of the two mucus layers in colon. Mice lacking the disulfide isomerase-like protein Agr2 have been shown to be more susceptible to colon inflammation. The Agr2(-/-) mice have less filled goblet cells and were now shown to have a poorly developed inner colon mucus layer. We could not show AGR2 covalently bound to recombinant MUC2 N- and C-termini as have previously been suggested. We found relatively high concentrations of Agr2 in secreted mucus throughout the murine gastrointestinal tract, suggesting that Agr2 may play extracellular roles. In tissue culture (CHO-K1) cells, AGR2 is normally not secreted. Replacement of the single Cys in AGR2 with Ser (C81S) allowed secretion, suggesting that modification of this Cys might provide a mechanism for circumventing the KTEL endoplasmic reticulum retention signal. In conclusion, these results suggest that AGR2 has both intracellular and extracellular effects in the intestine.
|
|
| 4. |
- Bergström, Joakim H., 1977, et al.
(författare)
-
Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG16
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:48, s. 13833-13838
-
Tidskriftsartikel (refereegranskat)abstract
- The small lectin-like protein ZG16 (zymogen granulae protein 16) aggregates bacteria and by that works together with the inner colon mucus layer to maintain bacteria at a safe distance from the epithelial cell surface. In the absence of Zg16, more bacteria penetrate the epithelium, enter the regional lymph nodes and spleen, trigger the immune system, and cause abdominal fat pad mass increase. ZG16 is important for a safe normal host-bacteria symbiosis as it does not kill commensal bacteria, but limit bacterial translocation into the host.
|
|
| 5. |
- Bergström, Joakim H., 1977
(författare)
-
Mucus associated proteins and their functional role in the distal intestine
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mammalian intestine, especially the large intestine, harbors complex societies of beneficial bacteria coexisting with the host. This is a mutualistic relationship, where the host provides nutrients and a favorable environment while the bacteria in return ferment indigestible polysaccharides to short chain fatty acids. The host needs to keep the bacteria at a safe distance from the intestinal cells to prevent disease. The first line of defense hindering these microorganisms from invading the underlying epithelium is a mucus layer built by the highly polymeric and heavily O-glycosylated MUC2 mucin, the main structural component. In the colon this mucus barrier is made up of two layers with similar composition. The outer layer is loose and easy removable while the inner is more dense and firmly adherent to the underlying epithelium. The inner layer is impermeable to bacteria and therefore separates the bacteria that reside in the lumen from the epithelial cells. In order to obtain a better understanding of the function and structure of this dynamic barrier we analyzed the mucus using proteomics based approaches to identify novel mucus components The focus of this thesis has been trying to understand the specific protective role of the MUC2 assosiated proteins in the mucus layer. Three proteins were chosen for further studies based on their abundance and production by the mucus secreting goblet cell. AGR2 belongs to the protein disulfide isomerase family, and has been proven important for proper MUC2 production. Using molecular biology tools and cell culture experiment it was shown that AGR2 does not covalently bind the MUC2 terminal recombinant proteins and that secretion of the molecule is dependent on an internal cysteine residue. The mucin-like protein FCGBP is a highly repetitive molecule that contains 13 von Willebrand D domains. Eleven of these contain an autocatalytic cleavage site that forms a new reactive C-terminus after cleavage, which occurs early during biosynthesis. ZG16 is a lectin-like molecule that has now been shown to bind peptidoglycan, the major bacterial cell wall component, via its carbohydrate recognition domain. It was shown that ZG16 is not bactericidal, but that it binds and aggregates Gram-positive bacteria and translocate them further out in the mucus. ZG16 is also able to bind to enterocytes via a protein receptor implying a novel sensory function. In summary, the results from this thesis demonstrate that these MUC2 associated proteins are important to form a functional protective mucus layer that prevents bacteria to reach the epithelium and by this cause disease.
|
|
| 6. |
- Bergström, Petra, et al.
(författare)
-
Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.
|
|
| 7. |
- Johansson, Malin E V, 1971, et al.
(författare)
-
Composition and functional role of the mucus layers in the intestine.
- 2011
-
Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 68, s. 3635-3641
-
Forskningsöversikt (refereegranskat)abstract
- In discussions on intestinal protection, the protective capacity of mucus has not been very much considered. The progress in the last years in understanding the molecular nature of mucins, the main building blocks of mucus, has, however, changed this. The intestinal enterocytes have their apical surfaces covered by transmembrane mucins and the whole intestinal surface is further covered by mucus, built around the gel-forming mucin MUC2. The mucus of the small intestine has only one layer, whereas the large intestine has a two-layered mucus where the inner, attached layer has a protective function for the intestine, as it is impermeable to the luminal bacteria.
|
|
| 8. |
- Lebrero-Fernandez, Cristina, et al.
(författare)
-
Murine Butyrophilin-Like 1 and BtnI6 Form Heteromeric Complexes in Small Intestinal Epithelial Cells and Promote Proliferation of Local T Lymphocytes
- 2016
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- To date, few molecular conduits mediating the cross talk between intestinal epithelial cells and intraepithelial lymphocytes (IELs) have been described. We recently showed that butyrophilin-like (BtnI) 1 can attenuate the epithelial response to activated IELs, resulting in reduced production of proinflammatory mediators, such as IL-6 and CXCL1. We here report that like BtnI1, murine BtnI6 expression is primarily confined to the intestinal epithelium. Although BtnI1 can exist in a cell surface-expressed homomeric form, we found that it additionally forms heteromeric complexes with BtnI6, and that the engagement of BtnI1 is a prerequisite for surface expression of BtnI6 on intestinal epithelial cells. In an IEL-epithelial cell coculture system, enforced epithelial cell expression of BtnI1 significantly enhanced the proliferation of IELs in the absence of exogenous activation. The effect on proliferation was dependent on the presence of IL-2 or IL-15 and restricted to IELs upregulating CD25. In the gamma delta T-cell subset, the BtnI1-BtnI6 complex, but not BtnI1, specifically elevated the proliferation of IELs bearing the V gamma 7V delta 4 receptor. Thus, our results show that murine epithelial cell-specific BtnI proteins can form intrafamily heterocomplexes and suggest that the interaction between BtnI proteins and IELs regulates the expansion of IELs in the intestinal mucosa.
|
|
| 9. |
- Rodríguez-Piñeiro, Ana María, et al.
(författare)
-
Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins.
- 2013
-
Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 305:5
-
Tidskriftsartikel (refereegranskat)abstract
- The mucus that protects the surface of the gastrointestinal tract is rich in specialized O-glycoproteins called mucins, but little is known about other mucus proteins or their variability along the gastrointestinal tract. To ensure that only mucus was analyzed, we combined collection from explant tissues mounted in perfusion chambers, liquid sample preparation, single-shot mass spectrometry, and specific bioinformatics tools, to characterize the proteome of the murine mucus from stomach to distal colon. With our approach, we identified ∼1,300 proteins in the mucus. We found no differences in the protein composition or abundance between sexes, but there were clear differences in mucus along the tract. Noticeably, mucus from duodenum showed similarities to the stomach, probably reflecting the normal distal transport. Qualitatively, there were, however, fewer differences than might had been anticipated, suggesting a relatively stable core proteome (∼80% of the total proteins identified). Quantitatively, we found significant differences (∼40% of the proteins) that could reflect mucus specialization throughout the gastrointestinal tract. Hierarchical clustering pinpointed a number of such proteins that correlated with Muc2 (e.g., Clca1, Zg16, Klk1). This study provides a deeper knowledge of the gastrointestinal mucus proteome that will be important in further understanding this poorly studied mucosal protection system.
|
|
