Open AccessAlterations in myeloid dendritic cell innate immune responses in the Gα i 2‐deficient mouse model of colitis
Author(s) -
Peña J.A.,
ThompsonSnipes L.,
Calkins P.R.,
Tatevian N.,
Puppi M.,
Finegold M.J.
Publication year - 2009
Publication title -
inflammatory bowel diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.932
H-Index - 146
eISSN - 1536-4844
pISSN - 1078-0998
DOI - 10.1002/ibd.20744
Subject(s) - innate immune system , immunology , tlr9 , dendritic cell , biology , colitis , myeloid , cytokine , immune system , microbiology and biotechnology , biochemistry , gene expression , dna methylation , gene
Background: The G protein alpha subunit type‐2 (Gα 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 Gα i 2 −/− 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 Gα i 2 −/− B6, Gα i 2 −/− 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 BMDCs induces sustained p38 MAPK activation and greater Th1‐ and Th17‐type cytokine secretion in both strains of Gα i 2‐deficient compared to wildtype BMDCs. However, only B6 Gα i 2 −/− BMDCs concomitantly produces IL‐10 while Gα i 2 −/− 129 BMDCs do not. Conclusions: Loss of Gα i 2 promotes a Th1/Th17 phenotype and relative IL‐10 insufficiency in Gα i 2 −/− 129 BMDCs may account for the striking difference in disease. (Inflamm Bowel Dis 2008)