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Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5

Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA

¹Correspondence: Center for Infection and Immunity, Mailman School of Public Health, Columbia University, 722 West 168th St., Rm. 1801, New York, NY, 10032 E-mail: wil2001{at}columbia.edu

RNA virus replication results in expression of double-stranded RNA (ds-RNA) molecules that trigger innate immune responses through interactions with both intracellular and extracellular receptors. We investigated the contributions of the extracellular and intracellular pathways to innate immunity in murine astrocyte primary cultures using polyinosinic-polycytidylic acid (poly I:C), a synthetic ds-RNA molecule designed to mimic RNA virus infection. Whereas extracellular poly I:C (naked poly I:C) mainly induced the expression of regulated on activation normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), and tumor necrosis factor (TNF-), intracellular delivery of poly I:C (complexed poly I:C) chiefly induced expression of IFN-β and IL-6. Experiments with astrocytes from Toll-like receptor 3 (TLR-3) knockout mice indicated that naked poly I:C signals via a TLR-3-dependent NF-B pathway. Complexed poly I:C induced the expression of the intracellular ds-RNA sensor proteins, retinoic acid inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA-5). However, transfection of astrocytes with dominant negative forms of the helicases implicated MDA-5, but not RIG-I, as the intracellular sensor of poly I:C. Complexed poly I:C-mediated MDA-5 stimulation transmitted "downstream" signals, resulting in activation of the transcription factors NF-B and IRF-3. Our results illustrate the intricacy of extracellular and intracellular ds-RNA recognition in viral infections of the central nervous system and indicate the importance of MDA-5 helicase as an intracellular ds-RNA sensor in astrocytes. De Miranda, J., Yaddanapudi, K., Hornig, M., Lipkin, W. I. Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5.

Key Words: ds-RNA • TLR-3 • RIG-I • CNS • innate immunity

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