TLR ligands up‐regulate Trex1 expression in murine conventional dendritic cells through type I Interferon and NF‐κB‐dependent signaling pathways. Issue 1 (5th March 2014)

• Record Type: Journal Article
• Authors: Xu, Jun; Zoltick, Philip W.; Gamero, Ana M.; Gallucci, Stefania
• Is Part Of: Journal of leukocyte biology. Volume 96:Issue 1(2014)
• Page Start: 93
• Page End: 103
• Publication Date: 2014-03-05
• Subjects: viral infection -- immune activation -- autoimmunity; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.2A0713-393RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : The regulation of Trex1 expression by TLRs, type I IFNs, and virus, implicates a novel role for Trex1 in DC immune activation. Abstract : Mutations in the Trex1 are associated with a spectrum of type I IFN‐dependent autoimmune diseases. Trex1 plays an essential role in preventing accumulation of excessive cytoplasmic DNA, avoiding cell‐intrinsic innate DNA sensor activation and suppressing activation of type I IFN‐stimulated and ‐independent antiviral genes. Trex1 also helps HIV to escape cytoplasmic detection by DNA sensors. However, regulation of Trex1 in innate immune cells remains elusive. We report that murine cDCs have high constitutive expression of Trex1 in vitro and in vivo in the spleen. In resting bone marrow‐derived cDCs, type I IFNs up‐regulate Trex1 expression via the IFNAR‐mediated signaling pathway (STAT1‐ and STAT2‐dependent). DC activation induced by TLR3, ‐4, ‐7, and ‐9 ligands also augments Trex1 expression through autocrine IFN‐β production and triggering of the IFN signaling pathway, whereas TLR4 ligand LPS also stimulates an early expression of Trex1 through IFN‐independent NF‐κB‐dependent signaling pathway. Furthermore, retroviral infection also induces Trex1 up‐regulation in cDCs, as we found that a gene therapy HIV‐1‐based lentiviral vector induces significant Trex1 expression, suggesting that Trex1 may affect local and systemic administration of gene‐therapy vehicles. Our data indicate that Trex1 is induced in cDCs during activation upon IFN and TLR stimulation through the canonical IFN signaling pathway and suggest that Trex1 may play a role in DC activation during infection and autoimmunity. Finally, these results suggest that HIV‐like viruses may up‐regulate Trex1 to increase their ability to escape immunosurveillance.