RESUMO
The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.
Assuntos
Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Vírus de DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Células RAW 264.7 , RNA Mensageiro/metabolismo , Succinatos/farmacologiaRESUMO
At the 2017 Keystone Symposia meeting, new research was presented in the fields of innate immunity and type I interferon regulation. Gathering experts from these research communities offered a unique opportunity to discuss new concepts and formulate novel approaches to modulate pathological mechanisms in human inflammatory diseases.