The transcription factor NFAT5 limits infection-induced type I interferon responses
Open Access
- 5 December 2019
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (3)
- https://doi.org/10.1084/jem.20190449
Abstract
Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.Funding Information
- Agencia Estatal de Investigación (SAF2015-71363-R, RTI2018-095902-B-I00, SAF2016-75505-R)
- Fundació la Marató TV3 (1225-30, 201619-30)
- Generalitat de Catalunya (2014SGR1153, 2017SGR888)
- Ministry of Economy and Competitiveness (MDM-2014-0370)
- Ministry of Education, Culture and Sports (FPU13/01798)
- Ministerio de Economy, Industry and Competitiveness (BES-2015-074170)
- Institució Catalana de Recerca i Estudis Avançats
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