Alterations in myeloid dendritic cell innate immune responses in the Gαi2-deficient mouse model of colitis
✍ Scribed by J.A. Peña; L. Thompson-Snipes; P.R. Calkins; N. Tatevian; M. Puppi; M.J. Finegold
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 996 KB
- Volume
- 15
- Category
- Article
- ISSN
- 1078-0998
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✦ Synopsis
Background:
The G protein alpha subunit type-2 (G␣ i 2)-deficient mouse develops inflammatory bowel disease (IBD) with increased severity in mice on a 129SvEv (129) background compared to the C57BL/6 (B6) background. Since dendritic cells (DCs) are key cells of innate immunity, we determined whether G␣ i 2 Ϫ/Ϫ DCs have functional defects, influenced by strain background, that predispose to IBD.
Methods:
By breeding these strains to homozygosity for the first time, it became possible to study innate immunity in this animal model with more precision than ever before. Immature DCs were generated using bone marrow monoblasts cultured in the presence of GM-CSF (BMDCs), DC subsets sorted and responses to TLR9 activation were assayed.
Results:
In contrast to G␣ i 2 Ϫ/Ϫ B6, G␣ i 2 Ϫ/Ϫ 129 mice display accelerated onset and increased severity of colitis, abnormal mucosal DC distribution, accompanied by preponderance for Th1 and Th17-associated gut cytokine expression. TLR9 activation of BM-DCs induces sustained p38 MAPK activation and greater Th1-and Th17-type cytokine secretion in both strains of G␣ i 2-deficient compared to wildtype BMDCs. However, only B6 G␣ i 2 Ϫ/Ϫ BMDCs concomitantly produces IL-10 while G␣ i 2 Ϫ/Ϫ 129 BMDCs do not.
Conclusions:
Loss of G␣ i 2 promotes a Th1/Th17 phenotype and relative IL-10 insufficiency in G␣ i 2 Ϫ/Ϫ 129 BMDCs may account for the striking difference in disease.