Ion Transport Basis of Diarrhea, Paneth Cell Metaplasia, and Upregulation of Mechanosensory Pathway in Anti-CD40 Colitis Mice.

Publisher: Oxford University Press Country of Publication: England NLM ID: 9508162 Publication Model: Print Cited Medium: Internet ISSN: 1536-4844 (Electronic) Linking ISSN: 10780998 NLM ISO Abbreviation: Inflamm Bowel Dis Subsets: MEDLINE

Publication: 2018- : [Oxford] : Oxford University Press
Original Publication: New York, NY : Raven Press, c1995-

Paneth Cells*/metabolism ; Paneth Cells*/pathology ; Colitis*/chemically induced ; Colitis*/metabolism ; Colitis*/pathology ; Metaplasia*/metabolism ; Metaplasia*/pathology ; Disease Models, Animal* ; Diarrhea*/metabolism ; Diarrhea*/pathology ; Mice, Knockout* ; Intestinal Mucosa*/metabolism ; Intestinal Mucosa*/pathology; Animals ; Mice ; CD40 Antigens/metabolism ; Up-Regulation ; Mice, Inbred C57BL ; Mechanotransduction, Cellular

Background: Anti-Cluster of differentiation (CD)-40-induced colitis, driven by innate inflammatory responses in the intestine, is a potent animal model exhibiting IBD pathophysiology including diarrhea. However, the ion transport basis of diarrhea and some key mucosal pathways (Paneth cells, stem cell niche, and mechanosensory) in this model have not been investigated.
Methods: Mucosal scrapings and intestinal tissue from control and CD40 antibody (150 µg) treated Rag2-/- mice were examined for gut inflammation, Paneth cell numbers, expression of key transporters, tight/adherens junction proteins, stem cell niche, and mechanosensory pathway via hematoxylin and eosin staining, quantitative polymerase chain reaction, and western blotting.
Results: Compared with control, anti-CD40 antibody treatment resulted in a significant loss of body weight (P < .05) and diarrhea at day 3 postinjection. Distal colonic tissues of anti-CD40 mice exhibited increased inflammatory infiltrates, higher claudin-2 expression, and appearance of Paneth cell-like structures indicative of Paneth cell metaplasia. Significantly reduced expression (P < .005) of downregulated in adenoma (key Cl- transporter), P-glycoprotein/multidrug resistantance-1 (MDR1, xenobiotic transporter), and adherens junction protein E-cadherin (~2-fold P < .05) was also observed in the colon of anti-CD40 colitis mice. Interestingly, there were also marked alterations in the stem cell markers and upregulation of the mechanosensory YAP-TAZ pathway, suggesting the activation of alternate regeneration pathway post-tissue injury in this model.
Conclusion: Our data demonstrate that the anti-CD40 colitis model shows key features of IBD observed in the human disease, hence making it a suitable model to investigate the pathophysiology of ulcerative colitis (UC).
(Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation 2024.)

I01 BX002867 United States BX BLRD VA; IK6 BX005242 United States BX BLRD VA; R01 DK054016 United States DK NIDDK NIH HHS; R56 DK092441 United States DK NIDDK NIH HHS; I01 BX002011 United States BX BLRD VA; I01 BX005862 United States BX BLRD VA; BX002011 Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; R01 DK 54016 NIH/NIDDK

Keywords: IBD; SLC26A3; innate immune response; intestinal inflammation; tight junction proteins
Local Abstract: [plain-language-summary] Our studies demonstrate the ion transport basis of diarrhea, downregulation of MDR1 and E-cadherin, Paneth cell metaplasia, and induction of claudin-2 and mechanosensory pathway in anti-CD40 colitis (innate immune-based model of IBD), similar to the human disease.

0 (CD40 Antigens)

Date Created: 20240201 Date Completed: 20240903 Latest Revision: 20240904

20240904

10.1093/ibd/izae002

38300738