In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells.
Cells from the mononuclear phagocyte system (MPS) act as systemic and local amplifiers that contribute to the progression of chronic inflammatory disorders. Transforming growth factor-β-activated kinase 1 (TAK1) is a pivotal upstream mitogen-activated protein kinase-kinase-kinase acting as a mediator of cytokine expression. It remains critical to determine in vivo the implication of TAK1 in controlling the innate immune system. Here, we describe a vehicle tailored to selectively deliver siRNAs into MPS cells after intravenous administration, and validate in vivo the potential of the RNAi-mediated TAK1 knock down for immunomodulation. In a mouse model of immune-mediated inflammatory disorder, we show that anti-TAK1 siRNA lipoplexes efficiently alleviate inflammation, severely impair the downstream c-Jun N-terminal kinase and nuclear factor-κB signaling pathways, and decrease the expression of proinflammatory mediators. Importantly, the systemic TAK1 gene silencing decreases the frequency of Th1 and Th17 cells, both mediating autoimmunity in experimental arthritis, demonstrating the immunomodulatory potential of TAK1. Finally, in vitro inhibition of TAK1 in myeloid cells decreases interferon-γ-producing T cells, suggesting that a delivery system able to target MPS cells and to silence TAK1 impacts on pathogenic T effector cells in autoimmunity.
Courties
Gabriel
G
INSERM U844, INM, Hôpital Saint Eloi, 80 rue Augustin Fliche, Montpellier, France. gabriel.courties@inserm.fr
Seiffart
Virginia
V
Presumey
Jessy
J
Escriou
Virginie
V
Scherman
Daniel
D
Zwerina
Jochen
J
Ruiz
Gisela
G
Zietara
Natalia
N
Jablonska
Jadwiga
J
Weiss
Siegfried
S
Hoffmann
Andrea
A
Jorgensen
Christian
C
Apparailly
Florence
F
Gross
Gerhard
G
D000818:Animals; D001168:Arthritis / Q000628:therapy; D002460:Cell Line; D007249:Inflammation / Q000628:therapy; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D034622:RNA Interference; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7