Background: In inflammatory bowel diseases (IBD), the epithelial barrier is impaired, leading to loss of ions and water as well as enhanced luminal antigen uptake supporting inflammation. Alterations in expression and localization of tight junction (TJ) proteins are known to be involved in these processes. While claudins like claudin-2 are linked to increased paracellular ion and water flux, explaining the symptom of leak-flux diarrhoea, less is known about the basis of increased antigen uptake leading to immune response.

Hypothesis: We hypothetize that besides being involved in luminal antigen uptake, the tTJ and its components may be also important in immune cell translocation and activation. It has been described that neutrophils and other leukocytes prefer tricellular corners for their passage and expression of tricellulin, but also of other TJ proteins, has been observed in cells of the monocyte/macrophage lineage. Based on these findings, we suggest an immunoregulatory role of TJ proteins and direct interaction between immune cells and TJs, especially tTJs.

Project: The doctoral thesis project we offer comprises characterizing the interaction of the (t)TJ barrier with subjacent immune-relevant cells and the mutual influence in developing IBD or inflammation in general. After isolating immune cells relevant for development and regulation of IBD and analyzing their potential expression profile of TJ proteins, direct interaction of the respective immune cells with their potential target TJ proteins will be visualized by live-cell confocal microscopy in cell lines expressing fluorescence-tagged TJ proteins. Interaction will be further characterized by higher resolved imaging techniques, by FRET (Förster resonance energy transfer), and by chemical coupling of the interacting partners and subsequent pulldown. The effect of immune response-activating substances will be analyzed to give insight into the regulation of tTJ permeability.

2^nd cohort PhD doctoral student

Lena Voges

• Voges L, Weiß F, Branco AT, Fromm M, Krug SM (2024) Expression and localization profiles of tight junction proteins in immune cells depend on their activation status. Int. J. Mol. Sci. 25(9): 4861 (18 pages), doi: 10.3390/ijms25094861 (°IF 4.9)

• Weiß F, Czichos C, Knobe L, Voges L, Bojarski C, Michel G, Fromm M, Krug SM (2022) MarvelD3 is upregulated in ulcerative colitis and has attenuating effects during colitis indirectly stabilizing the intestinal barrier. Cells 11: 1551 (16 pages) doi: 10.3390/cells11091541 (IF 6.0)

2^nd cohort MD doctoral student

Seymanur Yildirim

1^st cohort PhD doctoral student

Jia-Chen E. Hu
19.04.21: Doctoral examination passed,Dr. rer. nat. (PhD), Freie Universität Berlin, magna cum laude

Project-related publications

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1. Krug SM, Hayaishi T, Iguchi D, Watari A, Takahashi A, Fromm M, Nagahama M, Takeda H, Okada Y, Sawasaki T, Doi T, Yagi K, Kondoh M (2017) Angubindin-1, a novel paracellular absorption enhancer acting at the tricellular tight junction. J. Contr. Release 260: 1-11 [PubMed] [WebPage] [PDF] [Supplement]

2. Schütz A, Radusheva V, Krug SM*, Heinemann U* (*shared last authorship) (2017) Crystal structure of the tricellulin C-terminal coiled-coil domain reveals a unique mode of dimerization. Ann. N.Y. Acad. Sci. 1405: 147-159 [PubMed] [WebPage] [PDF] [Supplement]

3. Krug SM, Bojarski C, Fromm A, Lee IM, Dames P, Richter JF, Turner JR, Fromm M*, Schulzke JD* (*shared last authorship) (2018) Tricellulin is regulated via interleukin-13-receptor α2, affects macromolecule uptake, and is decreased in ulcerative colitis. Mucosal Immunol. 11(2): 345-356 [PubMed] [WebPage] [PDF] [Supplement] [Supplementary Movie]

4. Krug SM (2017) Contribution of the tricellular tight junction to paracellular permeability in leaky and tight epithelia. Ann. N.Y. Acad. Sci. 1317(1): 219-230 (°IF 4.7) [PubMed] [WebPage] [PDF]

5. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C (2017) Mend your fences: The epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell. Mol. Gastroent. Hepatol. 4(1): 33-46  [PubMed] [WebPage] [PDF] (Review)

6. Conrad MP*, Piontek J* (*shared first authorship), Günzel D, Fromm M, Krug SM (2016) Molecular basis of claudin-17 anion selectivity. Cell. Mol. Life Sci. 73(1): 185-200 [PubMed] [WebPage] [PDF] [Supplement]

7. Demehri FR*, Krug SM* (*shared first authorship), Feng Y, Lee IM, Schulzke JD, Teitelbaum DH (2016) Tight junction ultrastructure alterations in a mouse model of enteral nutrient deprivation. Dig. Dis. Sci. 61(6): 1524-1533  [PubMed] [WebPage] [PDF]

8. Yang S*, Krug SM* (*shared first authorship), Heitmann J, Hu L, Reinhold AK, Sauer S, Bosten J, Sommer C, Fromm M, Brack A*, Rittner HL* (*shared last authorship) (2016) Analgesic drug delivery via recombinant tissue plasminogen activator and mRNA-183-triggered opening of the blood-nerve barrier. Biomaterials 82: 20-33 [PubMed] [WebPage] [PDF] [Supplement]  

9. Richter JF, Schmauder R, Krug SM, Gebert A, Schumann M (2016) A novel method for imaging sites of paracellular passage of macromolecules in epithelial sheets. J. Contr. Release 229: 70-79 [PubMed] [WebPage] [PDF] [Supplement] [Movie S1] [Movie S2]

10. Krug SM, Schulzke JD, Fromm M (2014) Tight junction, selective permeability, and related diseases. Semin. Cell Devel. Biol. 36: 166-176 [PubMed] [WebPage] [PDF] (Review)

11. Krug SM, Amasheh M, Dittmann I, Christoffel I, Fromm M, Amasheh S (2013) Sodium caprate as an enhancer of macromolecule permeation across tricellular tight junctions of intestinal cells. Biomaterials 34(1): 275-282 [PubMed] [WebPage] [PDF]

12. Westphal JK, Dörfel MJ, Krug SM, Cording JD, Piontek J, Blasig IE, Tauber R, Fromm M, Huber O (2010) Tricellulin forms homomeric and heteromeric tight junctional complexes. Cell. Mol. Life Sci. 67(12): 2057-2068 [PubMed] [WebPage] [PDF] [Supplement]

13. Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol. Biol. Cell 20: 3713-3724 [PubMed] [WebPage] [PDF] [Supplement text] [Supplement video]

14. Krug SM, Fromm M, Günzel D (2009) Two-path impedance spectroscopy for measuring paracellular and transcellular epithelial resistance. Biophys. J. 97(8): 2202-2211 [PubMed] [WebPage] [PDF] [Supplement]