The exonuclease Trex1 restrains macrophage proinflammatory activation.
The three-prime repair exonuclease 1 (TREX1) is the most abundant exonuclease in mammalian cells. Mutations in Trex1 gene are being linked to the development of Aicardi-Goutières syndrome, an inflammatory disease of the brain, and systemic lupus erythematosus. In clinical cases and in a Trex1-deficient murine model, chronic production of type I IFN plays a pathogenic role. In this study, we demonstrate that Trex1(-/-) mice present inflammatory signatures in many different organs, including the brain. Trex1 is highly induced in macrophages in response to proinflammatory stimuli, including TLR7 and TLR9 ligands. Our findings show that, in the absence of Trex1, macrophages displayed an exacerbated proinflammatory response. More specifically, following proinflammatory stimulation, Trex1(-/-) macrophages exhibited an increased TNF-α and IFN-α production, higher levels of CD86, and increased Ag presentation to CD4(+) T cells, as well as an impaired apoptotic T cell clearance. These results evidence an unrevealed function of the Trex1 as a negative regulator of macrophage inflammatory activation and demonstrate that macrophages play a major role in diseases associated with Trex1 mutations, which contributes to the understanding of inflammatory signature in these diseases.
Grupo Biología del Macrófago, Departamento de Fisiología e Inmunología, Universitat de Barcelona, 08028 Barcelona, Spain.
Selma
S
Pereira-Lopes
Teja
T
Celhar
Gloria
G
Sans-Fons
Maria
M
Serra
Anna-Marie
AM
Fairhurst
Jorge
J
Lloberas
Antonio
A
Celada
D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D001923:Brain Chemistry; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D007739:L Cells; D008262:Macrophage Activation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010587:Phagocytosis; D010750:Phosphoproteins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016898:Interferon-alpha; D010750:Phosphoproteins; D011994:Recombinant Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1