title: Length of dsRNA (poly I:C) drives distinct innate immune responses, depending on the cell type.
abstract: Poly I:C, a synthetic dsRNA analogue, has been used extensively for decades to study innate responses in vivo and in different cell types. We have found substantial variability while using poly I:C from different sources. In this study we found that poly I:C from 2 commercial sources induced sharply opposite responses in myeloid and fibroblasts, depending on the length of the poly I:C. Although short poly I:C (≈ 1-1.5 kb) induced greater amounts of TNF-α, IL-8, and IFN-β and a stronger antiviral response in myeloid cells, it was a poor inducer in fibroblasts. By contrast, long poly I:C (>5 kb) preferentially elicited higher cytokine and antiviral responses in fibroblasts and showed diminished responses in myeloid cells. Poly I:C activated NF-κB and STAT-1 signaling in a length- and cell-type-dependent fashion. Mechanistically, short poly I:C was better internalized in the myeloid cells and long poly I:C in the fibroblasts. Finally, long poly I:C required SR-A, whereas short poly I:C required RIG-I and Raftlin. We provide evidence that the length of dsRNA drives distinct innate responses in different cell lineages. These findings may augment in selecting the appropriate poly I:C type to design cell-type-specific potent adjuvants for vaccines against infectious diseases or cancers.
authors.affiliation: 2.Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada. ashkara@mcmaster.ca.
authors.forename: M Firoz
authors.initials: MF
authors.lastname: Mian
authors.forename: Amna N
authors.initials: AN
authors.lastname: Ahmed
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Rad
authors.forename: Artem
authors.initials: A
authors.lastname: Babaian
authors.forename: Dawn
authors.initials: D
authors.lastname: Bowdish
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology*; D007370:Interferon Type I / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology; D011070:Poly I-C / Q000494:pharmacology*; D051117:Scavenger Receptors, Class A / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007155:Immunologic Factors; D007370:Interferon Type I; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D051117:Scavenger Receptors, Class A; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C
keywords: antiviral; cytokine; fibroblasts; internalization; myeloid cells