Alterations in myeloid dendritic cell innate immune responses in the Galphai2-deficient mouse model of colitis.
BACKGROUND
The G protein alpha subunit type-2 (Galpha(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 Galpha(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 Galpha(i)2(-/-) B6, Galpha(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 Galpha(i)2-deficient compared to wildtype BMDCs. However, only B6 Galpha(i)2(-/-) BMDCs concomitantly produces IL-10 while Galpha(i)2(-/-) 129 BMDCs do not.


CONCLUSIONS
Loss of Galpha(i)2 promotes a Th1/Th17 phenotype and relative IL-10 insufficiency in Galpha(i)2(-/-) 129 BMDCs may account for the striking difference in disease.
Peña
J A
JA
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Thompson-Snipes
L
L
Calkins
P R
PR
Tatevian
N
N
Puppi
M
M
Finegold
M J
MJ
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics*; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D012720:Severity of Illness Index
D016753:Interleukin-10; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse