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Immunol Lett ; 268: 106869, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38788802

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory intestinal disease that affects people around the world. The primary cause of IBD is an imbalance in the host immune response to intestinal flora. Several human genes, including IL10, STAT3, IRGM, ATG16L1, NOD2 and RUNX3, are associated with inappropriate immune responses in IBD. It has been reported that homozygous Runx3-knockout (ko) mice spontaneously develop colitis. However, the high mortality rate in these mice within the first two weeks makes it challenging to study the role of Runx3 in colitis. To address this issue, a spontaneous colitis (SC) mouse model carrying a C-terminal truncated form of Runx3 with Tyr319stop point mutation has been generated. After weaning, SC mice developed spontaneous diarrhea and exhibited prominent enlargement of the colon, accompanied by severe inflammatory cell infiltration. Results of immunofluorescence staining showed massive CD4+ T cell infiltration in the inflammatory colon of SC mice. Colonic IL-17A mRNA expression and serum IL-17A level were increased in SC mice. CD4+ T cells from SC mice produced stronger IL-17A than those from wildtype mice in Th17-skewing conditions in vitro. In addition, the percentages of Foxp3+ Treg cells as well as the RORγt+Foxp3+ Treg subset, known for its role in suppressing Th17 response in the gut, were notably lower in colon lamina propria of SC mice than those in WT mice. Furthermore, transfer of total CD4+ T cells from SC mice, but not from wildtype mice, into Rag1-ko host mice resulted in severe autoimmune colitis. In conclusion, the C-terminal truncated Runx3 caused autoimmune colitis associated with Th17/Treg imbalance. The SC mouse model is a feasible approach to investigate the effect of immune response on spontaneous colitis.


Subject(s)
Colitis , Core Binding Factor Alpha 3 Subunit , Disease Models, Animal , T-Lymphocytes, Regulatory , Th17 Cells , Animals , Th17 Cells/immunology , T-Lymphocytes, Regulatory/immunology , Mice , Colitis/immunology , Colitis/chemically induced , Colitis/genetics , Colitis/etiology , Core Binding Factor Alpha 3 Subunit/genetics , Core Binding Factor Alpha 3 Subunit/metabolism , Mice, Knockout , Humans , Autoimmune Diseases/immunology , Autoimmune Diseases/genetics , Autoimmune Diseases/etiology , Mice, Inbred C57BL , Interleukin-17/metabolism , Interleukin-17/genetics , Colon/pathology , Colon/immunology
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