Reply to: “Interferon regulatory factor 9 plays a dual function in health and disease”
Authors: Xiao-Jing Zhang, Pi-Xiao Wang, Peng Zhang, Hongliang Li
Journal: Journal of Hepatology (2015)

Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injuryJournal of HepatologyVol. 62Issue 1PreviewLiver ischemia and reperfusion (I/R) injuries arising from transplantation, trauma, or hypovolemic shock may cause liver failure or even multi-organ system failure [1]. Because cell death has long been viewed as a fundamental process that directly determines the extent of liver function damage in I/R injury, hepatocyte protection is a potential strategy for ameliorating I/R liver damage [2,3]. However, anti-apoptotic approaches are not widely used in existing therapies for liver I/R [4]. One possible reason is that the upstream mediators remain poorly defined in hepatocytes, even though considerable attention has been focused on apoptotic pathways [5]. Full-Text PDF Interferon regulatory factor 9 plays a dual function in health and diseaseJournal of HepatologyVol. 62Issue 6PreviewInterferon regulatory factor 9 (IRF9), as interferon-stimulated gene factor 3 gamma (ISGF3G), belongs to the IRF family and participates in a series of molecular pathways related to cell proliferation, oncogenesis, apoptosis, and innate immunity. IRF9 not only acts as a transcription factor, but also interacts with other transcription factors to regulate gene expression. However, IRF9 has a dual role in health and disease. Recently, the article by Wang et al. [1] showed that IRF9 overexpression aggravated the hepatic ischemia/reperfusion (I/R) injury and its deficiency significantly mitigated the symptoms after liver I/R. Full-Text PDF Open Access We appreciate Yu and Sun for their comments on our recent findings, which focused on the dual functions of interferon (IFN) regulatory factor 9 (IRF9) on cardiometabolic diseases.IRF9, also known as IFN-stimulated gene (ISG)F3γ or p48, belongs to the IRF family, which consists of nine members, IRF1-IRF9, in mammals [[1]Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar]. Since first being identified in 1990, IRF9 has been shown to be an essential regulator of the innate immune system and to stimulate the downstream genes of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) axis through its ability to form an ISGF3 complex with STAT1/STAT2 or STAT1/STAT1 [[2]Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Derived from its important location in the innate immune network, IRF9 is extensively involved in infectious conditions and autoimmune diseases [1Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar, 2Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Evolutionary reasoning has indicated that immune response is evolutionarily conserved and highly integrated into the metabolic system. The interaction and counterbalance between the immune and the metabolic systems form a central homeostasis, the dysfunction of which elicits a series of metabolic disorders, especially insulin resistance and obesity, as well as cardiovascular diseases [[3]Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (6120) Google Scholar]. A recent adopted perspective even presumed that cardiometabolic disease is a chronic low-grade inflammatory response [[4]Fernandez-Real J.M. Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome.Endocr Rev. 2003; 24: 278-301Crossref PubMed Scopus (720) Google Scholar]. Considering the important location of IRF9 in the innate immune network and the intimate connection between immune response and cardiometabolic disease, we questioned whether IRF9 can influence the pathogenesis of pathological cardiometabolic conditions, and if so, we wondered whether this function depends on immune regulation by IRF9.Interestingly, we recently uncovered a dramatic alteration in IRF9 expression in response to various cardiometabolic stresses, including ischemia/reperfusion (I/R) stimulation, vascular insult, hypertrophic stress and high-fat diet, suggesting that IRF9 is a susceptible cardiometabolic stress sensor that may affect these pathological conditions. Using genome-wide mRNA arrays and chromatin immunoprecipitation (ChIP) assays, we consequently highlighted a putative downstream target of IRF9, Sirt1, the promoter of which provides direct binding sites for IRF9. In response to I/R, the binding of IRF9 to Sirt1 downregulates Sirt1 transcriptional activity followed by enhanced acetylation and activation of p53, leading to aggravated cell death and exacerbation of tissue damage induced by hepatic, cerebral or myocardial I/R [5Chen H.Z. Guo S. Li Z.Z. Lu Y. Jiang D.S. Zhang R. et al.A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.J Neurosci. 2014; 34: 11897-11912Crossref PubMed Scopus (47) Google Scholar, 6Zhang Y. Liu X. She Z.G. Jiang D.S. Wan N. Xia H. et al.Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury.Basic Res Cardiol. 2014; 109: 434Crossref PubMed Scopus (43) Google Scholar, 7Wang P.X. Zhang R. Huang L. Zhu L.H. Jiang D.S. Chen H.Z. et al.Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury.J Hepatol. 2015; 62: 111-120Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Additionally, the IRF9-Sirt1 axis positively regulates activator protein (AP)-1 reporter activity, which significantly promotes vascular injury-induced neointima formation via enhanced vasculoproliferative pathology modulation [[8]Zhang S.M. Zhu L.H. Chen H.Z. Zhang R. Zhang P. Jiang D.S. et al.Interferon regulatory factor 9 is critical for neointima formation following vascular injury.Nat Commun. 2014; 5: 5160Crossref PubMed Scopus (47) Google Scholar]. Accordingly, we deduced that IRF9, as a classic transcriptional factor, could control transcriptional activation of downstream genes in response to cardiometabolic stresses. Another important fact to note is that IRF9 can act directly on parenchyma cells, not limited to immune or inflammatory cells. The target genes and cells of IRF9 suggest that, as a critical negative upstream regulator of Sirt1, IRF9 senses and regulates I/R and vascular insults through immune-independent mechanisms.A defining feature of transcription factors is that they regulate downstream programmes either through directly binding to target genes or through protein-protein interactions to regulate the transcriptional activity of other transcription factors. In addition to its binding capacity to downstream factor promoters, our subsequent studies demonstrated that IRF9 can influence the development of cardiometabolic diseases through interactions with other proteins [9Jiang D.S. Luo Y.X. Zhang R. Zhang X.D. Chen H.Z. Zhang Y. et al.Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin.Hypertension. 2014; 63: 119-127Crossref PubMed Scopus (68) Google Scholar, 10Wang X.A. Zhang R. Jiang D. Deng W. Zhang S. Deng S. et al.Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice.Hepatology. 2013; 58: 603-616Crossref PubMed Scopus (65) Google Scholar]. Our research group demonstrated that IRF9 competes with p300 for the binding domain of myocardin to disrupt its transcriptional activity and thereby reduces the hypertrophic response [[9]Jiang D.S. Luo Y.X. Zhang R. Zhang X.D. Chen H.Z. Zhang Y. et al.Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin.Hypertension. 2014; 63: 119-127Crossref PubMed Scopus (68) Google Scholar]. In diet-induced and genetically (ob/ob) obese mice, IRF9 directly interacts with peroxisome proliferator-activated receptor α (PPARα) and activates PPARα target genes, leading to amelioration of dyslipidaemia [[10]Wang X.A. Zhang R. Jiang D. Deng W. Zhang S. Deng S. et al.Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice.Hepatology. 2013; 58: 603-616Crossref PubMed Scopus (65) Google Scholar]. Therefore, as Yu and Sun pointed out, IRF9 is a cardiometabolic stimulus-response molecule that acts as a “double-edged sword” to regulate a cluster of cardiometabolic diseases due to their specific partners and corresponding molecular events (Fig. 1). Notably, although IRF9 is an immune regulator, additional mechanisms that are independent of its immune capacity have coevolved to regulate cell fate under pathological cardiometabolic conditions.The discovery of the cardiometabolic regulation of IRF9 prompts us to ask: ‘What about other IRFs?’ Intriguingly, our recent studies on IRF1, IRF3, IRF4, IRF7 and IRF8 have demonstrated that, like IRF9, certain IRFs exhibit stress-specific or cell-specific functions during cardiometabolic diseases through (but not limited to) an immune-independent manner. Furthermore, different IRFs exhibit inconsistent or even reverse phenotypes in certain cardiometabolic diseases, suggesting that overlapping and/or diverse IRF signallings might exist and form a complex network [1Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar, 2Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Thus, clarifying the crosstalk among different IRFs will offer illuminating glimpses into the applications of IRFs as novel therapeutic targets for cardiometabolic diseases. However, as transcriptional factors, IRFs are difficult to develop directly into pharmacological or genetic targets for disease treatment. Instead, upstream factors that determine when, where and how IRFs and their corresponding downstream events are activated/suppressed hold greater promise as possible approaches to treating these devastating conditions. Studies focusing on these important issues are in progress in our research group to fully understand the potential clinical applications of IRF signalling.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this letter. We appreciate Yu and Sun for their comments on our recent findings, which focused on the dual functions of interferon (IFN) regulatory factor 9 (IRF9) on cardiometabolic diseases. IRF9, also known as IFN-stimulated gene (ISG)F3γ or p48, belongs to the IRF family, which consists of nine members, IRF1-IRF9, in mammals [[1]Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar]. Since first being identified in 1990, IRF9 has been shown to be an essential regulator of the innate immune system and to stimulate the downstream genes of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) axis through its ability to form an ISGF3 complex with STAT1/STAT2 or STAT1/STAT1 [[2]Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Derived from its important location in the innate immune network, IRF9 is extensively involved in infectious conditions and autoimmune diseases [1Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar, 2Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Evolutionary reasoning has indicated that immune response is evolutionarily conserved and highly integrated into the metabolic system. The interaction and counterbalance between the immune and the metabolic systems form a central homeostasis, the dysfunction of which elicits a series of metabolic disorders, especially insulin resistance and obesity, as well as cardiovascular diseases [[3]Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (6120) Google Scholar]. A recent adopted perspective even presumed that cardiometabolic disease is a chronic low-grade inflammatory response [[4]Fernandez-Real J.M. Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome.Endocr Rev. 2003; 24: 278-301Crossref PubMed Scopus (720) Google Scholar]. Considering the important location of IRF9 in the innate immune network and the intimate connection between immune response and cardiometabolic disease, we questioned whether IRF9 can influence the pathogenesis of pathological cardiometabolic conditions, and if so, we wondered whether this function depends on immune regulation by IRF9. Interestingly, we recently uncovered a dramatic alteration in IRF9 expression in response to various cardiometabolic stresses, including ischemia/reperfusion (I/R) stimulation, vascular insult, hypertrophic stress and high-fat diet, suggesting that IRF9 is a susceptible cardiometabolic stress sensor that may affect these pathological conditions. Using genome-wide mRNA arrays and chromatin immunoprecipitation (ChIP) assays, we consequently highlighted a putative downstream target of IRF9, Sirt1, the promoter of which provides direct binding sites for IRF9. In response to I/R, the binding of IRF9 to Sirt1 downregulates Sirt1 transcriptional activity followed by enhanced acetylation and activation of p53, leading to aggravated cell death and exacerbation of tissue damage induced by hepatic, cerebral or myocardial I/R [5Chen H.Z. Guo S. Li Z.Z. Lu Y. Jiang D.S. Zhang R. et al.A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.J Neurosci. 2014; 34: 11897-11912Crossref PubMed Scopus (47) Google Scholar, 6Zhang Y. Liu X. She Z.G. Jiang D.S. Wan N. Xia H. et al.Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury.Basic Res Cardiol. 2014; 109: 434Crossref PubMed Scopus (43) Google Scholar, 7Wang P.X. Zhang R. Huang L. Zhu L.H. Jiang D.S. Chen H.Z. et al.Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury.J Hepatol. 2015; 62: 111-120Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Additionally, the IRF9-Sirt1 axis positively regulates activator protein (AP)-1 reporter activity, which significantly promotes vascular injury-induced neointima formation via enhanced vasculoproliferative pathology modulation [[8]Zhang S.M. Zhu L.H. Chen H.Z. Zhang R. Zhang P. Jiang D.S. et al.Interferon regulatory factor 9 is critical for neointima formation following vascular injury.Nat Commun. 2014; 5: 5160Crossref PubMed Scopus (47) Google Scholar]. Accordingly, we deduced that IRF9, as a classic transcriptional factor, could control transcriptional activation of downstream genes in response to cardiometabolic stresses. Another important fact to note is that IRF9 can act directly on parenchyma cells, not limited to immune or inflammatory cells. The target genes and cells of IRF9 suggest that, as a critical negative upstream regulator of Sirt1, IRF9 senses and regulates I/R and vascular insults through immune-independent mechanisms. A defining feature of transcription factors is that they regulate downstream programmes either through directly binding to target genes or through protein-protein interactions to regulate the transcriptional activity of other transcription factors. In addition to its binding capacity to downstream factor promoters, our subsequent studies demonstrated that IRF9 can influence the development of cardiometabolic diseases through interactions with other proteins [9Jiang D.S. Luo Y.X. Zhang R. Zhang X.D. Chen H.Z. Zhang Y. et al.Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin.Hypertension. 2014; 63: 119-127Crossref PubMed Scopus (68) Google Scholar, 10Wang X.A. Zhang R. Jiang D. Deng W. Zhang S. Deng S. et al.Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice.Hepatology. 2013; 58: 603-616Crossref PubMed Scopus (65) Google Scholar]. Our research group demonstrated that IRF9 competes with p300 for the binding domain of myocardin to disrupt its transcriptional activity and thereby reduces the hypertrophic response [[9]Jiang D.S. Luo Y.X. Zhang R. Zhang X.D. Chen H.Z. Zhang Y. et al.Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin.Hypertension. 2014; 63: 119-127Crossref PubMed Scopus (68) Google Scholar]. In diet-induced and genetically (ob/ob) obese mice, IRF9 directly interacts with peroxisome proliferator-activated receptor α (PPARα) and activates PPARα target genes, leading to amelioration of dyslipidaemia [[10]Wang X.A. Zhang R. Jiang D. Deng W. Zhang S. Deng S. et al.Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice.Hepatology. 2013; 58: 603-616Crossref PubMed Scopus (65) Google Scholar]. Therefore, as Yu and Sun pointed out, IRF9 is a cardiometabolic stimulus-response molecule that acts as a “double-edged sword” to regulate a cluster of cardiometabolic diseases due to their specific partners and corresponding molecular events (Fig. 1). Notably, although IRF9 is an immune regulator, additional mechanisms that are independent of its immune capacity have coevolved to regulate cell fate under pathological cardiometabolic conditions. The discovery of the cardiometabolic regulation of IRF9 prompts us to ask: ‘What about other IRFs?’ Intriguingly, our recent studies on IRF1, IRF3, IRF4, IRF7 and IRF8 have demonstrated that, like IRF9, certain IRFs exhibit stress-specific or cell-specific functions during cardiometabolic diseases through (but not limited to) an immune-independent manner. Furthermore, different IRFs exhibit inconsistent or even reverse phenotypes in certain cardiometabolic diseases, suggesting that overlapping and/or diverse IRF signallings might exist and form a complex network [1Zhao G.N. Jiang D.S. Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.Biochim Biophys Acta. 2015; 1852: 365-378Crossref PubMed Scopus (134) Google Scholar, 2Zhang X.J. Jiang D.S. Li H. Interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases.Br J Pharmacol. 2014; https://doi.org/10.1111/bph.12881Crossref Scopus (29) Google Scholar]. Thus, clarifying the crosstalk among different IRFs will offer illuminating glimpses into the applications of IRFs as novel therapeutic targets for cardiometabolic diseases. However, as transcriptional factors, IRFs are difficult to develop directly into pharmacological or genetic targets for disease treatment. Instead, upstream factors that determine when, where and how IRFs and their corresponding downstream events are activated/suppressed hold greater promise as possible approaches to treating these devastating conditions. Studies focusing on these important issues are in progress in our research group to fully understand the potential clinical applications of IRF signalling. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this letter. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this letter.