Type I interferon induced epigenetic regulation of macrophages suppresses innate and adaptive immunity in acute respiratory viral infection

Kroetz DN, Allen RM, Schaller MA, Cavallaro C, Ito T, Kunkel SL.

PLoS Pathog. 11(12):e1005338. 2015 Dec 28.

Speaker : Fang-Wei Liao (廖芳緯)                               Time: 15:10-16:00, Mar. 23, 2016

Commentator : Chia-Yi Yu, Ph.D. (余佳益 老師)       Place: Room 601

Abstract:

Alveolar macrophages (Mφ) are the first immune population to encounter influenza A virus (IAV) infection in the lungs and are indispensable for host protection. Previous studies suggest that epigenetic regulators involved in histone modification play critical roles in phenotypes and functions of Mφ. Notably, Setdb2, a tri-methyl transferase of lysine 9 of histone H3, is induced during IAV infection or type I interferon (IFN-I) treatment, but its role in regulation of innate and adaptive immune response during primary IAV infection remains unclear. In this study the authors found that Setdb2 was upregulated by IFN-I or IAV infection in murine and human Mφ, and that the Setdb2 upregulation required the JAK-STAT pathway and interferon regulatory factor 7 (IRF7). Using Setdb2^LacZ reporter mice, they revealed that IFN-I induced Setdb2 expression in Mφ in vitroand majorly in myeloid cells in the lungs during IAV infection in vivo. Accordingly, the authors generated Setdb2^ff Lyz2^cre+ mice with Setdb2 deficiency specifically in myeloid cells. Such Setdb2 deficiency enhanced survival during lethal IAV infection, concurrently with decreased viral load, reduced airway obstruction, and increased lymphoid cell clustering near blood vessels. The IFN-I-stimulated BM-Mφ isolated from Setdb2^ff Lyz2^cre+ mice expressed antiviral genes (including Isg15 and Mx1), chemokines (including CCL2), and cytokines (including IL-6 and IL-12p40) at higher levels, and the elevated gene expression was associated with reduced repressive histone methylation and enhanced transcription factor recruitment to the target promoters. In addition, CD4⁺ T cells cocultured with Setdb2^-/- BM-Mφ produced more T_H1 cytokines, suggesting that Setdb2 expression in Mφ also influences T cell activation. Combined with a recent study showing that Setdb2 reduces host defense against bacterial superinfection, this study supports that Setdb2 is an attractive therapeutic target for controlling primary IAV infection and its secondary bacterial infection.

References:

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