IFN-β Therapy Regulates TLR7-Mediated Response in Plasmacytoid Dendritic Cells of Multiple Sclerosis Patients Influencing an Anti-Inflammatory Status.
Plasmacytoid dendritic cells (pDCs) display altered immune-phenotype in multiple sclerosis (MS) patients and are found actively recruited in postmortem MS brain lesions, implying that their immune regulation may represent an important aspect of MS pathogenesis. Because of the reported Toll-like receptor 7 (TLR7) implication in autoimmunity, in this study we characterized how IFN-β therapy impacts on pDC activation to TLR7 triggering in MS patients, aspect only poorly investigated so far. In vivo IFN-β administration regulates pDC functions in TLR7-treated peripheral blood mononuclear cell (PBMC) cultures differently from what is observed in isolated cells, suggesting that IFN-β may activate inhibitory mechanisms in MS peripheral blood involved in turning off pDC response to dampen the ongoing inflammation. Indeed, IL-10, a key regulatory cytokine found increased upon TLR7 stimulation in in vivo IFN-β-exposed PBMCs, directly reduced pDC-mediated IFN-α production. IFN-β therapy also shaped T-cell responses by decreasing TLR7-induced pDC maturation and inducing T-cell inhibitory molecules. Accordingly, raised pDC-induced IL-27 and decreased IL-23 expression, together with high IL-10 level, contribute to inhibit Th17 cell differentiation. Our study uncovered a role for IFN-β in the regulation of TLR7-mediated pDC responses in MS toward an anti-inflammatory phenotype opening new opportunities to better understand mechanisms of action of this drug in controlling MS immunopathogenesis.
1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità , Rome, Italy .
Martina
M
Severa
1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità , Rome, Italy .
Fabiana
F
Rizzo
1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità , Rome, Italy .
Elena
E
Giacomini
2 Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University , Rome, Italy .
Viviana
V
Annibali
1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità , Rome, Italy .
Valerie
V
Gafa
2 Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University , Rome, Italy .
Silvia
S
Romano
2 Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University , Rome, Italy .
Maria Chiara
MC
Buscarinu
2 Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University , Rome, Italy .
Arianna
A
Fornasiero
2 Centre for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital Site, Sapienza University , Rome, Italy .
Marco
M
Salvetti
1 Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità , Rome, Italy .
Eliana Marina
EM
Coccia
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D064094:Interleukin-27 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
D000893:Anti-Inflammatory Agents; C508609:IL10 protein, human; D007155:Immunologic Factors; D016898:Interferon-alpha; D053759:Interleukin-23; D064094:Interleukin-27; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016753:Interleukin-10; D016899:Interferon-beta