Abstract
Previous studies have shown that single-stranded RNA (ssRNA) mixed with protamine forms particles and activates immune cells through Toll-like receptors (TLRs). We have found that the size of protamine-RNA particles generated depends on the electrolyte content when mixing the 2 components. Moreover, we have evidenced that (1) nanometric particles induce production of interferon-alpha, whereas (2) micrometric particles mainly induce production of tumor necrosis factor-alpha (TNF-alpha) in human immune cells. We found that the mechanisms underlying these observations are (1) nanoparticles but not microparticles are selectively phagocytosed by plasmacytoid dendritic cells (pDCs), which produce interferon-alpha and (2) monocytes that produce TNF-alpha have a higher activation threshold than that of pDCs. Thus, at the same time as sensing pathogen-associated molecular patterns such as ssRNA, the immune system distinguishes the size of the associated structure in such a way as to trigger the adapted antivirus (nanometric) or antibacterial/antifungal (micrometric) immune response. Our results introduce a new dimension in danger signaling--how size qualitatively affects innate response.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adjuvants, Immunologic / chemistry
-
Adjuvants, Immunologic / genetics
-
Adjuvants, Immunologic / pharmacology
-
Animals
-
Base Sequence
-
Dendritic Cells / immunology
-
Humans
-
Immunity, Innate
-
In Vitro Techniques
-
Interferon-alpha / biosynthesis
-
Membrane Glycoproteins / deficiency
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Nanoparticles / chemistry
-
Oligodeoxyribonucleotides / chemistry
-
Oligodeoxyribonucleotides / genetics
-
Oligodeoxyribonucleotides / immunology
-
Oligodeoxyribonucleotides / pharmacology
-
Particle Size
-
Phagocytosis
-
Protamines / chemistry
-
Protamines / immunology
-
RNA / chemistry*
-
RNA / genetics
-
RNA / immunology*
-
RNA / pharmacology
-
RNA Stability
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Toll-Like Receptor 7 / deficiency
-
Toll-Like Receptor 7 / genetics
-
Toll-Like Receptor 7 / immunology
-
Tumor Necrosis Factor-alpha / biosynthesis
Substances
-
Adjuvants, Immunologic
-
CPG-oligonucleotide
-
Interferon-alpha
-
Membrane Glycoproteins
-
Oligodeoxyribonucleotides
-
Protamines
-
Tlr7 protein, mouse
-
Toll-Like Receptor 7
-
Tumor Necrosis Factor-alpha
-
RNA