Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules.
DAP12 (also known as KARAP) is a novel ITAM-bearing transmembrane adapter molecule that is expressed on the cell surface of natural killer cells, monocytes, dendritic cells, and macrophages. Several myeloid cell-specific DAP12-associating receptors, such as TREM receptor family, SIRP-beta1, and MDL-1 have been identified. The in vivo function of DAP12 and its associating molecules in inflammation has remained primarily unknown. To investigate DAP12 signaling during chronic inflammation, we constructed two adenoviral gene transfer vectors to express FLAG/DAP12 (Ad-FDAP12) and the extracellular domain of mouse TREM-1 and the Fc portion of human IgG1 (Ad-TREM-1 Ig), respectively, and observed their modulatory activities in a mouse model of hepatic granulomatous inflammation elicited by zymosan A. Mice were injected with zymosan A intravenously and 24 hours after zymosan A, they were injected with Ad-FDAP12 or Ad-TREM-1 Ig. Zymosan A-induced hepatic granuloma formation peaked at day 7 and markedly declined by day 10. Although adenoviral-mediated DAP12 gene transfer did not enhance granuloma formation by day 7, it sustained and enhanced granuloma formation beyond day 7. However, an anti-FLAG monoclonal antibody used to potentiate the signaling of adenoviral-derived DAP12, enhanced granuloma formation at day 7. In sharp contrast to the effect by Ad-FDAP12, transgene expression in the liver of soluble form of extracellular domain of TREM-1 as an antagonist of DAP12 signaling, remarkably inhibited zymosan A-induced granuloma formation at all time points examined. Our findings thus suggest that both DAP12 and TREM-1 are involved in the development of granulomatous responses in the liver.
Nochi
Hitoshi
H
Department of Pathology, Asahikawa Medical College, Asahikawa, Japan.
Aoki
Naoko
N
Oikawa
Kensuke
K
Yanai
Mitsuru
M
Takiyama
Yumi
Y
Atsuta
Yoshiaki
Y
Kobayashi
Hiroya
H
Sato
Keisuke
K
Tateno
Masatoshi
M
Matsuno
Takeo
T
Katagiri
Makoto
M
Xing
Zhou
Z
Kimura
Shoji
S
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors; D006099:Granuloma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007694:Killer Cells, Natural / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000235:genetics*; D015398:Signal Transduction; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D001616:beta-Galactosidase / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D007141:Immunoglobulin Fc Fragments; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C498715:TREM2 protein, human; C110546:TYROBP protein, human; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D001616:beta-Galactosidase