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Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils¹

Nicola Tamassia^*, Vincent Le Moigne^*, Marzia Rossato^*, Marta Donini^*, Stephen McCartney, Federica Calzetti^*, Marco Colonna, Flavia Bazzoni^* and Marco A. Cassatella^2,*

^* Department of Pathology, University of Verona, Verona, Italy; and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Neutrophils, historically known for their involvement in acute inflammation, are also targets for infection by many different DNA and RNA viruses. However, the mechanisms by which they recognize and respond to viral components are poorly understood. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic mimetic of viral dsRNA that is known to interact either with endosomal TLR3 (not expressed by human neutrophils) or with cytoplasmic RNA helicases such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). In this study, we report that intracellularly administered poly(I:C) stimulates human neutrophils to specifically express elevated mRNA levels encoding type I IFNs, immunoregulatory cytokines, and chemokines, such as TNF-, IL-12p40, CXCL10, CXCL8, CCL4, and CCL20, as well as classical IFN-responsive genes (IRG), including IFIT1 (IFN-induced protein with tetratricopeptide repeats 1)/IFN-stimulated gene (ISG)56, G1P2/ISG15, PKR (dsRNA-dependent protein kinase), and IFN-regulatory factor (IRF)7. Investigations into the mechanisms whereby transfected poly(I:C) promotes gene expression in neutrophils uncovered a crucial involvement of the MAPK-, PKR-, NF-B-, and TANK (TNF receptor-associated NF-B kinase)-binding kinase (TBK1)/IRF3-signaling transduction pathways, as illustrated by the use of specific pharmacological inhibitors. Consistent with the requirement of the cytoplasmic dsRNA pathway for antiviral signaling, human neutrophils were found to constitutively express significant levels of both MDA5 and RIG-I, but not TLR3. Accordingly, neutrophils isolated from MDA5-deficient mice had a partial impairment in the production of IFN-β and TNF- upon infection with encephalomyocarditis virus. Taken together, our data demonstrate that neutrophils are able to activate antiviral responses via helicase recognition, thus acting at the frontline of immunity against viruses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (COFIN and 60% funds), Fondazione Cassa di Risparmio di Verona-Vicenza-Ancona e Belluno and Associazione Italiana per la Ricerca sul Cancro (AIRC).

² Address correspondence and reprint requests to Dr. Marco A. Cassatella, Department of Pathology, Division of General Pathology, Strada Le Grazie 4, 37134 Verona, Italy. E-mail address: marco.cassatella{at}univr.it

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; CHX, cycloheximide; DC, dendritic cell; EMCV, encephalomyocarditis virus; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; IKK, IB kinase; IRF, IFN regulatory factor; IRG, IFN-responsive gene; ISG, IFN-stimulated gene; MDA5, melanoma differentiation-associated gene 5; MMP, matrix metalloproteinase; MNE, mean normalized expression; MOI, multiplicity of infection; mono-DC, monocyte-derived DC; PKR, dsRNA-dependent protein kinase; poly(I:C), polyinosinic:polycytidylic acid; PT, primary transcript; RIG-I, retinoic acid-inducible gene I; TBK, TANK (TNF receptor-associated NF-B kinase)-binding kinase; TRAF, TNFR-associated factor; TRIF, TIR-domain-containing adapter-inducing IFN-β.

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