Preferential expression and function of Toll-like receptor 3 in human astrocytes.
In contrast to other tissues, the central nervous system (CNS) is essentially devoid of MHC expression and shielded from antibodies by the blood-brain barrier. Therefore, a rapid local innate immune response by resident brain cells is required to effectively fight infectious agents. This study analyzed the expression and function of Toll-like receptors (TLRs) in cultured human astrocytes. Quantitative PCR for TLRs 1 to 10 showed a basal expression of TLR3 that could be enhanced by IFN-gamma, IL-1beta, and IFN-beta. The other TLRs were barely detectable and not inducible by the same cytokines. IFN-gamma-activated astrocytes responded to TLR3 ligand poly (I:C) engagement with IL-6 production, while ligands of other TLRs, like LPS, lipoteichoic acid, peptidoglycan, flagellin, and CpG, had no effect. Poly (I:C) also triggered astrocyte production of TNF-alpha and the chemokines CCL2/MCP-1, CCL5/RANTES, CCL20/MIP-3alpha, and CXCL10/IP-10. The adapter molecules MyD88 (full length and short isoform), TIRAP/Mal, and TICAM-1/TRIF, which are required for TLR signaling, were all expressed by astrocytes. Thus, resting and activated human astrocytes express preferentially TLR3 and, upon TLR3 engagement, produce IL-6 and chemokines active on T cells, B cells, monocytes, and dendritic cells. These data indicate that astrocytes function as sentinels for viral infections in the CNS.
Farina
Cinthia
C
Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Krumbholz
Markus
M
Giese
Thomas
T
Hartmann
Gunther
G
Aloisi
Francesca
F
Meinl
Edgar
E
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000096:biosynthesis; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D011070:Poly I-C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C408982:CPG-oligonucleotide; D018925:Chemokines; D015850:Interleukin-6; D008024:Ligands; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C