Immunostimulatory CpG-DNA Activates Murine Microglia

• Published in: The Journal of immunology (1950) 2002-05, Vol.168 (10), p.4854-4863
• Main Authors: Dalpke, Alexander H, Schafer, Martin K.-H, Frey, Markus, Zimmermann, Stefan, Tebbe, Johannes, Weihe, Eberhard, Heeg, Klaus
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - antagonists & inhibitors; Adjuvants, Immunologic - pharmacology; Animals; Brain - immunology; Brain - metabolism; Cell Line; Cell Line, Transformed; CpG Islands - immunology; DNA, Bacterial - administration & dosage; DNA, Bacterial - antagonists & inhibitors; DNA, Bacterial - pharmacology; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation - immunology; Injections, Intraperitoneal; Injections, Intraventricular; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Interleukin-12 - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microglia - enzymology; Microglia - immunology; Microglia - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - antagonists & inhibitors; Oligodeoxyribonucleotides - pharmacology; Phagocytosis - immunology; Poly G - metabolism; Poly G - pharmacology; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; RNA, Messenger - biosynthesis; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.10.4854

Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-DNA) triggers innate immune cells through the pattern recognition receptor Toll-like receptor 9 (TLR-9). CpG-DNA possesses potent immunostimulatory effects on macrophages, dendritic cells, and B lymphocytes. Therefore, CpG-DNA contributes to inflammation during the course of bacterial infections. In contrast to other TLR-dependent microbial patterns, CpG-DNA is a strong inductor of IL-12. Thus, it acts as a Th1-polarizing agent that can be utilized as potent vaccine adjuvant. To assess the role of CpG-DNA in immune reactions in the CNS, we analyzed the effects of CpG-DNA on microglial cells in vitro and in vivo. Primary microglial cells as well as microglial cell lines express TLR-9 mRNA. Consequently, CpG-DNA activated microglial cells in vitro and induced TNF-alpha, IL-12p40, IL-12p70, and NO. Furthermore, MHC class II, B7-1, B7-2, and CD40 molecules were up-regulated. In addition, phagocytic activity of microglia was enhanced. After intracerebroventricular injection of CpG-DNA, microglial cells were activated and produced TNF-alpha and IL-12p40 transcripts, as shown by in situ hybridization. These results indicate that microglia is sensitive to CpG-DNA. Thus, bacterial DNA containing CpG motifs could not only play an important role during infections of the CNS, but also might trigger and sustain Th1-dominated immunopathogenic reactions.