IRFs in Heart: Stress Response Beyond Inflammation

Cardiac hypertrophy and pathological remodeling are hallmarks of cardiomyopathy associated with many pathological stressors, such as mechanic overload, oxidative injury, hormonal stimulation or viral infection. Transcriptional regulation is key to this process, involving well established transcription factors, such as NFAT, GATA, MEF2, and NF-kB among others¹. They function as the downstream effectors for upstream signaling to alter the cardiac transcriptome that ultimately leads to pathological changes in cardiomyocyte morphology and function. Therefore, uncovering the molecular basis of the regulatory circuit for cardiac gene expression has been a major focus of intense research efforts. In this issue, a study from Dr. Hongliang Li’s laboratory expands the complexity of the transcriptional network in the heart by uncovering yet another new player from an unexpected family ².

Interferon regulatory factors (IRF) are a group of transcription factors that were first identified for their inducible expression in response to interferon signaling³. Members of the IRF family play critical roles in anti-viral responses, inflammatory regulation, cytokine signaling, cell death, growth and differentiation³. Interferon exerts potent anti-pathogen responses in the host immune system, and have been employed as therapeutic agents against viral infections, such as hepatitis C⁴. The link between interferon function and heart disease was first observed in interferon based anti-viral therapies where interferon alpha treatment was reported to cause transient or irreversible cardiomyopathies^5-7. In contrast, conflicting effects of interferon gamma were observed in both clinical and animal studies. Whereas interferon gamma treatment was beneficial for viral-induced myocarditis⁸, it was also reported to cause cardiomyopathy and dysfunction in transgenic mice⁹. Genetic knockout of interferon gamma receptor reduced AngII induced hypertrophy and remodeling. In contrast, genetic ablation of interferon gamma enhanced pathological hypertrophy and diastolic heart failure ^{10, 11}. These functional impacts of interferon on cardiac hypertrophy and pathological remodeling raise important questions about the role of downstream IRFs in cardiac pathology. Do they affect cardiomyocytes indirectly via infiltrating inflammatory cells or do they function directly to regulate cardiac hypertrophy and remodeling in cardiomyocyte in a cell-autonomous fashion? More importantly, are IRFs involved specifically in interferon triggered cardiomyopathy or broadly in other pathological stress responses in the heart? A series of recent reports from Dr. Hongliang Li’s laboratory began to address these questions based on sophisticated genetic analysis both in cultured myocytes and intact mouse hearts.

In the study published in the current issue of Hypertension ², Jiang et al found the IRF7 expression in heart was down-regulated upon pressure-overload induced by aortic banding. Similar down-regulation of IRF7 expression was observed in cultured cardiomyocytes following Angiotensin II or phenylephrine treatment, indicating that IRF7 expression in cardiomyocytes can be regulated in response to a broad spectrum of pathological stressors, perhaps in an interferon independent manner. By both genetic ablation and cardiac specific over-expression in mice, the authors further revealed an inhibitory effect of IRF7 on the cardiac hypertrophy and associated pathological changes in response to pressure-overload. By demonstrating a similar effect in cultured myocytes, Jiang et al established a cell-autonomous effect for IRF7 in regulating cardiac hypertrophy under different pathological stressors. Following similar experimental approaches, the same group has also implicated other IRF members, including the role of IRF4, IRF9 and IRF3 in cardiac hypertrophy regulation. In particular, IRF9 and IRF3 share similar anti-hypertrophic effects as IRF7 ^{12, 13}, whereas IRF4 appears to possess opposite functions in the heart¹⁴. Altogether, these findings clearly indicate that the IRF family members are potentially important new players in cardiac gene regulation in the onset of pathological hypertrophy and remodeling.

Despite of their shared impact on cardiac hypertrophy and remodeling, the underlying mechanisms involved in each IRF family members appear to be significantly different. Whereas IRF4 promotes cardiac hypertrophy at least in part via transcriptional induction of cAMP Response Element Binding Protein (CREB) ¹⁴, IRF9 and IRF3 inhibit cardiac hypertrophy via targeted manipulation of myocardin and MAP kinase (ERK) activities, respectively ^{12, 13}. In contrast, Jiang et al report here that IRF7 directly interacts with IKKβ and inhibits hypertrophy via negative regulation of the NF-κB pathway ². Clearly, although originally discovered as transcription factors, IRF members also possess diverse function as signaling modulators for transcription factors and protein kinases. This is also in line with their established diverse functions in anti-pathogen responses and inflammatory regulation. Therefore, it is tempting to speculate that the IRF members (IRF7, IRF9 and IRF3) with inhibitory effects on cardiac hypertrophy may be mobilized as a coordinated compensatory response to pathological stresses in the heart by targeting different but complementary pathways in hypertrophy, involving NF-κB, myocardin and ERK(Figure 1).

Figure 1.

Illustration of IRF 3, IRF4, IRF7 and IRF9 function in cardiac hypertrophy and remodeling, and demonstrated targets of their activity in cardiomyocytes based on references^{2, 12-14}.

These findings on IRFs function in heart highlight the complexity of cardiac regulatory network and raise more interesting questions for future investigation. Although these reports from Dr. Li’s laboratory focus mainly on cardiac hypertrophy and remodeling induced by mechanical overload, the role of IRFs in physiological hypertrophy in response to exercise or pregnancy remains untested. Based on the observation of largely normal cardiac phenotypes in genetic ablation models, it is likely that IRFs have a limited role in normal cardiac differentiation and growth during development. Rather, IRFs mediated signaling may be specifically related to pathological stress responses in the heart, a speculation that needs to be further investigated experimentally. Furthermore, considering the importance of downstream pathways implicated in IRF function, the functional impact of IRFs in acute stress response such as myocardial infarction would be an interesting question to pursue. Finally, beyond the heart, CREB, ERK and IKKβ are widely expressed in different tissues. It is not clear if these interactions are common mechanisms for each IRF across different tissues, or a unique mechanism only manifested in the specific context of the cardiomyocyte. If similar mechanisms exist in other tissues, IRFs may function beyond their originally defined interferon regulation in inflammatory cells, but rather as a family of universal stress-response genes implicated in different tissues and pathological conditions. The creation of genetic models with tissue-specific manipulation of the IRF members, such as in the current report, will be powerful tools to investigate the expanding universe of IRF function in different issue and diseases.

With insights learned from IRF function in the pathologically stressed heart, we can now explore the potential therapies by targeted manipulation of IRFs. In the report by Jiang et al, manipulation IRF7 expression or downstream NF-kB pathway achieved significant impact on disease progression in pressure-overloaded hearts ². Similar efforts targeted to other IRF members, by either augmenting the function of IRF3 and 9 or inhibiting that of IRF4, also exerted protective effect in heart ^12-14. However, it is still untested whether such manipulations can reverse established cardiac hypertrophy or pathological remodeling. Clearly, with the finding of IRFs as new regulators of pathological hypertrophy and remodeling in heart, we can anticipate more research in this area to advance our current understanding the pathological stress response in the diseased heart.