TLR7/9 signs are capable of mounting massive interferon (IFN) response in
TLR7/9 signs are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. for pDC-mediated antiviral response. Introduction By detecting the presence of foreign nucleic acids, plasmacytoid DCs (pDCs) play crucial roles in the induction of both innate and adaptive immune responses (Reizis et al., 2011a; Lewis and Reizis, 2012; Merad et al., 2013; Karrich et al., 2014; Mildner and Jung, 2014; Swiecki and Colonna, 2015). Despite their rare presence in the lymphoid organs and circulating blood, pDCs are superior IFN producers and immediate responders to viral contamination (Reizis et al., 2011b; Ng et al., 2013; Swiecki and Colonna, 2015; Webster et al., 2016). After pDC depletion, the early IFN response to both DNA viruses (HSV, mouse hepatitis virus, and murine CMV) and RNA viruses (vesicular stomatitis virus [VSV] and respiratory syncytial virus) was severely impaired (Lund et al., 2006; Smit et al., 2006; Swiecki et al., 2010, 2013; Takagi et al., 2011; Cervantes-Barragan et al., 2012). Moreover, the pDC-induced IFN response has been shown to be critically involved in the induction of T cell response required for controlling chronic contamination by lymphocytic choriomeningitis virus (Blasius et al., 2012; Cervantes-Barragan Sirt6 et al., 2012). In this regard, pDC depletion or dysfunction has been linked to a variety of human chronic infections, especially the infections caused by HIV (Chehimi et al., 2002; Li et al., 2014; Zhang et al., 2015b), hepatitis W virus (Duan et al., 2004), and hepatitis C virus (Decalf et al., 2007). In addition to viral nucleic acids, pDCs can recognize self-DNAs/RNAs released by necrotic cells, and thus have been implicated in the pathogenesis of autoimmune diseases including systemic lupus erythematosus and psoriasis (Lande et al., 2007; Ganguly et al., 2009, 2013; Rowland et al., 2014; Sisirak et al., 2014). However, how pDCs are genetically and epigenetically programmed for IFN response remains incompletely comprehended. Compared with other immune cells, the most remarkable feature of pDCs rests in their unique expression of endosomal sensors TLR7/9 and massive IFN-producing capacity. Unlike TLR3/4 signals, which depend on transcriptional factor IRF3 to induce IFN response, TLR7/9 signals activate IRF7, as well as transcriptional factors NFB and AP-1, to elicit IFN/ production (Kawai et al., 2004). Interestingly, it seems that IRF7 has a more fundamental Angiotensin III (human, mouse) role than IRF3 in mounting IFN response to a broad spectrum of viruses (Honda et al., 2005), and IRF7 deficiency can lead to recurrent influenza contamination in humans (Ciancanelli et al., 2015). Although most cells express IRF7 only after viral contamination through feedback IFN/ signaling, pDCs are capable of expressing IRF7 in the steady state (Sato et al., 2000; Izaguirre et al., 2003; Ning et al., 2011). Because both pDCs and IRF7 play such a pivotal role in IFN response, how pDCs manage to express IRF7 constitutively needs to be precisely defined. Indeed, some recent findings have begun to shed light on this issue. Transcriptional factors E2-2 and STAT3 not only are essential for pDC development and maintenance, but also are critically involved in IRF7 expression in the steady state (Laouar et al., 2003; Ghosh et al., 2010; Li et al., 2012). Conversely, DNA methylation of CpG-containing island (CGI) encompassing promoter has been shown to be involved in silencing expression in human fibroblasts (Lu et al., 2000). However, whether this layer of epigenetic regulation also operates in immune cells remains uncharacterized. CpG islands enriched for CpG dinucleotides are present in Angiotensin III (human, mouse) 70% of mammalian gene promoters. Not surprisingly, CGIs can profoundly shape chromatin structure, thereby participating in the regulation of gene expression. Although CpG islands are frequently hypomethylated or Angiotensin III (human, mouse) unmethylated in somatic cells, and mostly associated with active gene transcription, mounting evidence suggests that CGIs can become hypermethylated in certain immune cells, and more frequently in malignant.