Furong Qing,Zhiping Liu
Interferon regulatory factor 7 in inflammation, cancer and infection
IRF7,interferon,inflammation,cancer,infection
Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factors (IRFs) family, is located downstream of the pattern recognition receptors (PRRs)-mediated signaling pathway and is essential for the production of type I interferon (IFN-I). Activation of IRF7 inhibits various viral and bacterial infections and suppresses the growth and metastasis of some cancers, but it may also affect the tumor microenvironment and promote the development of other cancers. Here, we summarize recent advances in the role of IRF7 as a multifunctional transcription factor in inflammation, cancer and infection by regulating IFN-I production or IFN-I-independent signaling pathways.
Interferon regulatory factor 7 in inflammation, cancer and infection

Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factors (IRFs) family, is located downstream of the pattern recognition receptors (PRRs)-mediated signaling pathway and is essential for the production of type I interferon (IFN-I). Activation of IRF7 inhibits various viral and bacterial infections and suppresses the growth and metastasis of some cancers, but it may also affect the tumor microenvironment and promote the development of other cancers. Here, we summarize recent advances in the role of IRF7 as a multifunctional transcription factor in inflammation, cancer and infection by regulating IFN-I production or IFN-I-independent signaling pathways.

Interferon regulatory factors (IRFs) are a class of transcription factor families that share a conserved N-terminal DNA-binding domain (DBD) and an IRF-associated structural domain (IAD) (1, 2). Currently, there are 11 members of IRFs. The mammalian IRFs consist of IRF1-9 (3), whereas IRF10 and IRF11 are only found in avian or fish (4, 5).The main role of IRFs is to regulate the transcription of Interferon (IFN) and the expression of IFN stimulated genes (ISGs). Thereby they promote the production of inflammatory cytokines and chemokine (6). Specifically, when this family member is activated by phosphorylation, it can further activate IFN and the expression of ISGs through the JAK-STAT pathway, and promote the production of inflammatory cytokines, which are widely involved in apoptosis, tumorigenesis and viral latency (7–9). In addition, the IAD structural domain at the C-terminus of IRFs can interact with other members of the family and other transcription factors including NF-κB and PU.1 to play important roles in host defense against viruses and bacteria, in innate and acquired immune responses, and in cell development and tumorigenesis (10). Interferon regulatory factor 7 (IRF7) is a member of the IRFs. IRF7 gene is located on human chromosome 11p15.5 and encodes four isoforms of IRF7A, -B, -C and -D (-H) (11), which can be constitutively expressed in the spleen, lymph nodes and bone marrow and especially in epithelial cells, monocytes and macrophages. Recognition of pathogenic microorganisms by pattern recognition receptors (PRRs) induces the activation and translocation of IRF7 to nuclear, leading to IFN-I production and secretion. Then IFN-I can be recognized and bound by IFNAR receptors on the cell surface. Subsequently, IRF7 production is induced via the JAK-STAT signaling pathway. This results in an IRF7-IFN-I positive feedback loop that allows for the sustained production of large amounts of IFN. However, many studies have shown that there are both promoting and inhibiting effects of IFN in diseases such as inflammation, cancer, and infection (12, 13). Therefore, by understanding the role of IRF7 in inflammation, cancer and infection, we can develop the new means to better regulate the function of IRF7 and modulate the immune response in a more precise and effective manner. More importantly, it will enable the development of highly targeted therapies for clinical use. However, systemic review of IRF7 in inflammation, cancer and infection is still lacking.

The IRF7 gene, originally identified in 1997 during latent EB virus (EBV) infection, encodes a protein that binds to and regulates the EB-Barr virus nuclear antigen 1 (EBNA-1) Q promoter (14) and is closely related to the major EBV oncogenic protein latent membrane protein-1 (LMP-1) (15). It has been shown that IRF7 can be activated by phosphorylation through TBK1/IKKϵ and TRIF-dependent pathways downstream of the cytoplasmic RNA/DNA sensor, and subsequently enters the nucleus, dimerizes with IRF3, exerts transcriptional activation and induces IFN-α/β expression (16). IRF7 is also essential for the induction of IFN-α/β gene expression via the viral-activated MyD88 independent pathway and the TLR-activated MyD88-dependent pathway (16). IRF7 is a positive regulator of IFN-I gene induction downstream of PRRs (17) and the positive feedback loop formed by IRF7-IFN-I allows for the continuous production of large amounts of IFN, which ultimately resists infection by pathogenic microorganisms ( Figure 1 ).

Inflammation is a host defensive response to detrimental stimuli. Usually, inflammation is an automatic and beneficial defense response. However, overt inflammation can be harmful, such as attacking on the body’s own tissues. Large amounts of cytokines, chemokines during inflammation could play important roles in the development of various diseases. IRF7 can promote inflammation and the development of inflammatory diseases. Systemic sclerosis (SSc) is a multi-system autoimmune disease characterized by vasculopathy, fibrosis and immune system dysregulation. However, there are currently no targeted treatment options for the fibrotic complications of SSc, and disease-related mortality remains high (18). A study showed that the gene and protein levels of IRF7 were significantly enhanced in skin and cultured fibroblasts from patients with SSc. Furthermore, IRF7 promotes TGF-β-induced fibrosis by interacting with Smad3 in fibroblasts. Specifically, in comparison with wild-type (WT) mice, IRF7 knockout (Irf7-/- ) mice showed lower IL-6 gene expression levels, lower expression of pro-fibrotic factors in fibroblasts, less subcutaneous thickness, and milder inflammatory responses, and thus less skin fibrosis after bleomycin stimulation (19). Both type 2 helper T (Th2) cells and type 2 innate lymphoid cells (ILC2s) are major driver of allergic airway inflammation or asthma. Patients with asthma displayed higher levels of ILC2s in both peripheral blood and bronchoalveolar lavage fluid (BALF) compared to healthy individuals (20). Another study showed that IRF7 expression in murine lung ILC2s was dramatically induced upon stimulation of papain or interleukin-33 (IL-33). ILC2s from asthma patients display a markedly higher level of IRF7 than those from healthy donors, indicating that IRF7 might enhance the development of asthma. Furthermore, IRF7 deficiency in mice attenuated the various allergic asthma animal models through limiting the expansion and function of lung ILC2s by inhibiting the expression of BCL11B and other cytokines such as IL-13 and IL-5 (21). Similarly, IRF7, together with IRF3, was shown to promote RAPTOR and mTOR activation and inhibit autophagy, which in turn enhanced lung inflammation and injury induced by diesel exhaust particles (DEPs) (22). However, IRF7 is also able to suppress inflammation and inhibit the development of inflammatory diseases in other circumstances. Pulmonary hypertension (PH) is a severe syndrome characterized by the extensive remodeling of small intrapulmonary arteries, leading to the development of right ventricular hypertrophy and dysfunction and, eventually, lethal right heart failure (23). Current treatment options primarily improve the symptoms or slow disease progression, but they cannot cure this severe condition. Thus, the development of more effective treatments is urgently warranted (24). Using an MCT-induced in vivo rat model of PH and in vitro rat pulmonary artery smooth muscle cells (PASMCs), IRF7 was able to inhibit NF-κB activation resulting in a significant reduction in the levels of pro-inflammatory cytokines such as TNF-α and IL-6, as well as inhibit ATF3 signaling to reduce the proliferation of PASMCs and their resistance to apoptosis. These results suggest that IRF7 can prevent vascular remodeling in pulmonary arterial hypertension by inhibiting the proliferation and inflammation of PASMCs (25). Overall, transcription factors are key factors that regulate the inflammatory response (26). Notably, IRF7 is a multifunctional transcription factor, and plays pro-inflammatory or anti-inflammatory roles in different inflammatory diseases through various signaling pathways, such as NF-κB signaling pathway, autophagy activation, etc. ( Figure 2 ). The specific role of IRF7 in inflammation may vary depending on the microenvironment ( Table 1 ).

As a multifunctional transcription factor, IRF7 can regulate cell differentiation, proliferation, and apoptosis in addition to being involved in immune regulation. Therefore, IRF7 plays an important role in tumor development and metastasis (10). IRF7 can act as a tumor suppressor that inhibits the proliferation and metastasis of cancer cells. A study showed that overexpression of IRF7 increased IFN-β production and significantly enhanced NK cell activity, leading to cytolysis of prostate cancer cells and exerting a role in limiting bone metastasis of prostate cancer (27). Another study on different gastric cancer cell lines revealed that the activation of circ0007360/miR-762/IRF7 axis suppressed the survival, migration and invasion of gastric cancer cells, indicating the inhibitory role of IRF7 in gastric cancer (28). A further study showed that miR-762 can directly target the 3′ UTR of IRF7 mRNA and inhibit IRF7 expression and in turn promotes the proliferation and invasion of breast cancer cells (29). Meanwhile, miR-1587 can downregulate IRF7 expression to promote the polarization of tumor-associated macrophages (TAMs) to M2 type, which produces anti-inflammatory factors to promote immune escape, proliferation and migration of breast cancer cells, and thus enhancing breast cancer development (35). IRF7 was also shown to inhibit the expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs) through directly suppressing S100A9 expression, thus reducing lung cancer metastasis (30). Interestingly, IRF7 can also act as an oncogene that promotes cancer development. IRF7 was shown to promote glioma cell invasion as well as chemoresistance and radiation resistance by inhibiting the expression of argonaute 2 (AGO2), a regulator of microRNA maturation, biosynthesis, and function (31). Another study showed that lncRNA AFAP1-AS1 promoted non-small cell lung cancer (NSCLC) cell proliferation, invasion and migration while inhibiting cell apoptosis. Meanwhile, lncRNA AFAP1-AS1 can activate IRF7, indicating that IRF7 can promote cell proliferation (36). A further study found that Circ-EGLN3 could act as an endogenous competitive RNA (ceRNA) to enhance the expression of IRF7 by competitively binding miR-1299, which in turn promoted the cell proliferation and invasion and the development of renal cell carcinoma (37). In addition, IRF7 can upregulate the expression of anti-inflammatory genes such as IL10 and downregulate pro-inflammatory genes such as IL1B, TNF, CXCL1 and CXCL2 to polarize microglia to the M2 type, thereby establishing a tumor microenvironment that exerts immunosuppressive effects. Meanwhile, IRF7 mediates STAT3 expression and promotes the survival and stem cell differentiation potential of glioblastoma multiforme (GBM) cells through the IL-6-STAT3 signaling pathway, and then enhances the progression and invasion of GBM. Notably, IRF7 promotes the conversion of microglia to M2 type, a pathway that can be inhibited by TGFβ1 (32–34). As mentioned above, IRF7 plays different roles in different tumor progressions. It can act as a tumor suppressor to kill cancer cells by promoting NK cell activity or to function downstream of cancer cell miRNAs (27, 28). IRF7 can also downregulate the expression of S100A9 and reduce the aggregation of G-MDSCs to limit the metastasis and spread of cancer cells (30). In addition, it can restrict the polarization of tumor-associated macrophages to M2 macrophages, thus preventing the proliferation, migration and metastasis of cancer cells (35). IRF7 can also act as a pro-oncogene to inhibit the expression of microRNA regulators and apoptosis of cancer cells. Meanwhile, it can promote IL-6-STAT3 signaling to induce cancer cells to acquire stem cell differentiation potential (33). Moreover, it can regulate the phenotypic transition of microglia and enhance the expression of anti-inflammatory genes, thereby inducing cancer cell proliferation, invasion and immune escape (32) ( Figure 3 ). Therefore, the role of IRF7 in cancer development may be different in various conditions ( Table 1 ).

Innate antiviral signaling mainly activates IRF3, IRF7 and NF-κB signaling to induce IFN and other pro-inflammatory factors to inhibit viral replication and propagation. Irf7-/- mice infected with Venezuelan equine encephalitis virus (VEEV) had significantly lower survival rates and higher viral loads in liver, spleen and brain tissues compared to WT mice due to reduced IFN-I production (44). Compared to WT mice, Irf7-/- mice exhibited higher lethality, less IFN-I production, and early and elevated viral loads in peripheral and central nervous system tissues after West Nile virus (WNV) infection. Consistent with this, there was reduced IFN-α production and increased viral titers in Irf7-/- progenitor macrophages, fibroblasts, dendritic cells, and cortical neurons (45). Another study showed that IRF7 silencing inhibited the production of IFN-α and IFN-β, while IRF7 could act in combination with CCL7 to increase neutrophil and macrophage infiltration and therefore enhancing antiviral response induced by rhinovirus RV infection (46). Influenza A virus inhibited p53-IRF7-IFN-γ signaling, resulting in diminished expression of antiviral molecules such as MX2 and EIF2AK2, leading to immune escape (47). IRF7 promotes the production of IFN-α and is also able to downregulate the expression of RELA, a member of the NF-κB family, thereby inhibiting the replication of human immunodeficiency virus (HIV) in cervical tissue (48). Notably, IRF7 was shown to attenuate chronic infection by limiting the establishment of herpes C virus latency and viral reactivation in the peritoneal cavity and, to a lesser extent, in the spleen (51). Some studies investigated the relation between IRF7 and SARS-CoV-2. Single-cell RNA-seq analysis of neutrophils from COVID-19 patients revealed that excessive activation of neutrophils in critically ill patients was significantly and positively correlated with the expression of IRF7. That is, activation of IRF7 promoted neutrophil production of inflammatory cytokines during SARS-CoV-2 infection, leading to the development of an inflammatory cytokine storm. IRF7 signaling blockade effectively reduced neutrophil inflammation during SARS-CoV-2 infection. Noteworthy, IRF7 expression was positively correlated with SARS-CoV-2 RNA load in virus-positive neutrophils (49). However, another study found that patients with autosomal recessive IRF7 deficiency had reduced type I and type III IFN production by respiratory epithelial cells and plasmacytoid dendritic cells, and were highly susceptible to SARS-CoV-2 infection (50). Interestingly, IRF7 deficient mice were unable to control lymphocytic choriomeningitis virus (LCMV) replication due to reduced IFN-I production in the early stages of infection. However, in the late stages of infection, they did mount a normal CD4+ T cell response, a relatively normal CD8+ T cell response, enabling the clearance of LCMV infection to a degree consistent with that of WT mice (52). Another study also found that CD8+ T cell recruitment to the CNS and clearance of LCMV were IRF7-independent (53). These indicate that IRF7 may not play an intrinsic role in the activation of T cells. In short, IRF7 enhances the host defense against RNA viral infection by promoting IFN-I production in both acute and chronic phases. However, some viruses are able to undergo immune escape by targeting IRF7. For example, Seneca Valley Virus (SVV) induced degradation of IRF3 and IRF7 proteins and inhibited transcription of IFN-α, IFN-β, and ISGs, thus leading to immune escape of the virus (54). African swine fever virus (ASFV) MGF505-7R inhibited IFN-β and ISRE promoter activity and the expression of IFN-I and ISGs by degrading IRF7 and TBK1, thereby evading the host antiviral response (55). VP23 protein from Marek’s disease virus (MDV) inhibited IRF7 phosphorylation and nuclear translocation, leading to reduced IFN-β production and ultimately immune escape (56). These also show that IRF7 is important in inducing a positive feedback loop in IFN and viral immune escape.

IRF7 plays an important role in the host defense against bacterial infection by regulating IFN-I. A study found that protein tyrosine phosphatase-1B (PTP1B) deficiency could enhance ISRE and the production of cytokine and chemokine, thus increase host clearance of Pseudomonas aeruginosa. Meanwhile, it was found that PTP1B deficiency induce the expression of IRF7, indicating that IRF7 could increase host defense against P. aeruginosa infection by promoting the production of IFN-I (38). When weakly virulent Mycobacterium tuberculosis infects macrophages, it can activate IRF3 and IRF7, resulting in increased IFN-I production and thus controlling the infection, while strongly virulent M. tuberculosis inhibits IRF7 expression and produces cytokine storm due to its ability to activate Oasl1, a negative regulator of IFN-I, which ultimately leads to cell death of macrophage, indicating the inhibitory role of IRF7 in M. tuberculosis infection (39). Other studies also found that upregulation of IRF7 through the activation of cGAS-STING-TBK1-IRF3/IRF7 and RIG-I-MAVS-IRF7 signaling pathways can promote IFN-β expression and directly inhibits M. tuberculosis infection (40, 41).

Given its multifunctional transcription factor activity, IRF7 also has an important role in host defense against parasitic infections. IRF7 was reported to promote IFN-I expression and enhances intestinal epithelial antimicrobial defense against Cryptosporidium parvum infection (42). Interestingly, IRF7 was shown to impair early splenic CD4+ Th1 cell activation, thereby promoting infection by blood-stage Plasmodium ( 43). Therefore, the role of IRF7 in parasitic infections remains to be characterized. In conclusion, IRF7 plays a predominantly resistant role in bacterial and viral infections and has both a facilitative and inhibitory role in parasitic infections, which may be related to the different cells or signaling pathways ( Figure 4 , Table 1 ).

A rapid, precise and ordered cellular response is central for host defense against pathogens and tumors. IRF7 plays a crucial role as an important transcriptional regulator of cellular responses in a variety of inflammatory diseases, cancers and infections. IRF7, a major regulator of IFN-I, exerts different biological functions and activities in various inflammation-related diseases. IRF7 can be either a tumor suppressor or an oncogene. As an interferon regulatory factor, IRF7 also plays a key role in host defense against bacterial, parasitic and viral infections. However, its role in fungal infections has not been well characterized. It is undeniable that IRF7 plays a key role in host defense against various bacterial and viral infections by promoting the production of IFN-I. However, many studies have now proposed other functions for IRF7. As a transcription factor, IRF7 can directly induce the expression of inflammatory cytokines and autophagy by promoting mTOR signaling pathway. IRF7 also plays an important role in immune escape, cell proliferation and survival of tumor cells by affecting macrophage polarization, NK cell activation, apoptosis, and G-MDSC cell aggregation. Interestingly, IRF7 can be regulated by some MicroRNAs and also affects certain MicroRNA regulators in the tumor microenvironment. A study showed that, miR-541 promoted vascular smooth muscle cell proliferation by targeting IRF7 (57). In contrast, miR-144 was shown to target the TRAF6-IRF7 axis, whose activation attenuates the host response to influenza virus infection. This indicates that mechanisms to induce IRF7 activity by microRNAs, directly or indirectly, exist (58). In addition, IRF7 is subject to ubiquitination modifications during viral infection. TRIM21 affects IRF7 stability downstream of viral TLRs in order to limit antiviral responses (59). Like TRIM21, the E3 ligase RAUL adds K48 linked ubiquitin chains to both IRF3 and IRF7 and ultimately acts as a brake on the system in response to viral infection (60).Therefore, whether IRF7, as a transcription factor, promotes or inhibits disease development by directly or indirectly regulating additional molecules deserves further exploration; whether IRF7, as an interferon regulator, functions independently of IFN-I or through IFN-II or IFN-III in inflammation, cancer and infection remains unclear. In conclusion, IRF7 is a multifunctional regulator that not only mediates the production of IFN-I, but also regulates autophagy, apoptosis and cell activation, and proliferation. Therefore, IRF7 plays different roles in various diseases, which may result from activation of multiple signaling pathways. It deserves more investigations to study the regulatory mechanisms of IRF7 and the signaling pathways of the IRF system, which may become important targets for the treatment of infectious diseases, inflammation-related diseases or cancer.

Original idea and planning: ZL, Writing. FQ Reviewing and editing—ZL. All authors contributed to the article and approved the submitted version.