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Interferon regulatory factors: Where to stand in transplantation
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Review
Interferon regulatory factors: Where to stand in transplantation Sara Assadiasla, , Abbas Shahib, Saeedeh Salehib, Shima Afzalib, Aliakbar Amirzargara,b ⁎
a b
Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
ARTICLE INFO
ABSTRACT
Keywords: Interferon regulatory factor Transplantation Rejection Ischemia reperfusion injury
Interferon regulatory factors (IRFs) are implicated in regulating inflammatory responses to pathogens and alloantigens. Since transplantation is usually accompanied by ischemia reperfusion injury (IRI), acute and chronic rejections, as well as immunodeficiency due to immunosuppressive drugs, IRFs seem to play a considerable role in allograft outcome. For instance, IRF-1 has been shown to be involved in pathogenesis of IRI; however, IRF-2 exhibits an opposite function. Some IRF-3 and 5 SNPs are associated with better or worse graft survival rates. Of note, IRF-4 inhibition has resulted in improved transplant outcomes. Herein we review available studies about IRFs influence on various stages of transplantation.
1. Introduction Solid organ and stem cell transplantation have recently been considered as the main modalities in treating end stage organ damage and various life-threatening hematologic disorders. However, despite all surgical and pharmacological advancements, recipients' survival rate and quality of life are not satisfying enough. In fact, adverse effects of immunosuppressive (IS) drugs such as hyperglycemia, dyslipidemia, osteoporosis,gastrointestinal complications, along with the increased risk of infection, lymphoproliferative disorders and skin malignancies turn them into a secondary challenge after transplantation [1]. Therefore, many efforts have been made to relieve the patients from lifelong medications or replace currently used drugs with those of less toxicity. Among all studied ideas, specific manipulation of immune system for inhibiting exaggerated responses to alloantigens has been considered as the most appropriate option. In order to achieve this goal there is no way but identifying functional details of every single immune component involved in graft rejection or tolerance [2]. In this regard, recently some encouraging findings have been published about IRF-4 inhibition in transplantation and as a result considerable promotion in cardiac allograft survival, which brought the idea of targeting these molecules to regulate immune responses specifically and efficiently with fewer metabolic side effects [3,4]; therefore, we decided to review all available studies about different IRFs correlation with transplantation. Interestingly, there were remarkable findings which deserved to be shared in order to provoke further investigations for defining whether IRFs could be eligible candidates for future therapeutic strategies or not.
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Interferon regulatory factors (IRFs) implication in pathogenesis of autoimmunity and malignancies has already been investigated and some members of this family have been shown to be directly contributed to certain disease, for instance IRF6 expression has a negative correlation with breast cancer invasiveness and several IRF polymorphisms which increase their expression have been recognized to be involved in Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD) and Systemic lupus erythematosus (SLE) pathogenesis [5,6]. Regarding interferon regulatory factors profound implication in immune cells development and activation in addition to their prominent association with autoimmune diseases, it is time to understand their function in transplantation. 2. Interferon regulatory factors The family of IRF transcription factors includes nine members of IRF1–9, all sharing a common DNA binding domain (DBD) structure. DBD consists of approximately 115 amino acids composed of several five-tryptophan sequences which form a helix-turn-helix structure involved in binding to INF-stimulated response element (ISRE) on target DNA. Contrary to similar DBD site, the carboxy-terminal region is different between IRFs for instance, there is an IRF-associated domain 2 (IAD2) in variable part of IRF-1 and 2, but the rest of IRFs contain IAD1 (Fig. 1) [5]. IRFs were first recognized as type 1 interferon (IFN) genes transcription factors but later their involvement in producing IFN-γ, oncogenesis, metabolism and immune cells development was demonstrated. They are also involved in pathogen recognition receptors (PRR)
Corresponding author at: Molecular immunology research center, Children's Medical Center, 62 Qarib St., Keshavarz Blvd., Tehran 14194, Iran. E-mail address: [email protected] (S. Assadiasl).
https://doi.org/10.1016/j.trim.2018.10.001 Received 14 August 2018; Received in revised form 10 October 2018; Accepted 12 October 2018 0966-3274/ © 2018 Elsevier B.V. All rights reserved.
Please cite this article as: Assadiasl, S., Transplant Immunology, https://doi.org/10.1016/j.trim.2018.10.001
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Fig. 1. Schematic illustration of different interferon regulatory factor (IRF) molecules structure.
of IRF-1 contribution to the IRI. Tsung et al. studied a group of mice which were subjected to hepatic ischemia for 60 min; they demonstrated that IRF-1 knockout mice were resistant to IRI as compared to the control mice which displayed significantly higher expression levels of TNF-α, IL-6 and ICAM-1, in addition to the elevated amounts of inducible nitric oxide synthase (iNOS). Besides, adenoviral delivery of IRF-1 gene into the knockout mice resulted in considerable tissue injury following ischemia induction. So they suggested a principal role for IRF1 in IRI [13]. Later, Kim et al. injected IRF-1-expressing adenovirus (AdIRF-1) and control gene vector (Adnull) to the two groups of donor rats 4 days prior to the harvesting, and then transplanted transduced livers to the normal rats. Two days later, recipients from AdIRF-1 rats showed elevated levels of liver enzymes along with increased expression of IFN-β, IFN-δ, IL-12, and iNOS. Moreover, overexpression of IRF1 resulted in augmented activation of JNK/MAP kinase signaling pathway in addition to enhanced hepatocellular apoptosis and necrosis [14]. Consistent with these results, Yokota and colleagues demonstrated better liver transplant outcomes from IRF-1 knockout mice. IL15 and IL-15Rα mRNA expression, as well as NK, NKT, and CD8+ T cells population were reduced in allograft. Furthermore, they evaluated human hepatocytes before and after transplantation and reported IRF-1 overexpression following ischemia in these cells; IL-15 and IL-15Rα expression showed to be upregulated in an IRF-1–dependent manner. Moreover, after human IRF-1 gene silencing ischemia-related inflammation was resolved, the effect which was demonstrated to be reversible by IL-15/IL-15Rα complexes induction, so they suggested IL15 and IL-15Rα overexpression due to IRF-1 upregulation as an underlying mechanism for ischemia reperfusion injury [15]. A similar study showed that liver transplantation from IRF-1 knockout mice to wild type is accompanied by significantly lower levels of TRAIL (TNFrelated apoptosis-inducing ligand), DR5 (Death receptor5), Fas, FasL and IFN-γ expression in allograft comparing to the control model (WT to WT). Moreover, caspase-8 activity was inhibited in KO to WT model. These findings provide more evidence for IRF-1 contribution to the post-transplant insults [16]. Additionally, it has been demonstrated that maturation of liver plasmacytoid dendritic cells (pDC) is augmented by ischemia reperfusion. These cells promote IRF-1 expression through IFN-α secretion which consequently provokes IL-6 and TNF-α production together with hepatocytes apoptosis. To confirm these findings, they showed that applying anti-IFN-α mAb 30 min before ischemia resulted in IRF-1 inhibition and protected the liver tissue from IRI. In vivo depletion of pDCs using anti-mPDCA-1 pure-functional grade mAb
signaling to chromatin for immune cells activation. Although most IRFs are mainly expressed in immune cells and play a significant role in T, B, NK, as well as dendritic cells maturation and function, some members like IRF- 3, 4, 5, 7 and 8 have been found to express in kidney, liver and heart tissue participating in pathogenesis of metabolic disorders [7,8]. 2.1. IRF-1 One of the first studies about IRF-1 impact on transplant outcome was performed by Afrouzian et al. who observed better survival rates in mice receiving wild type renal allograft comparing to the group which were transplanted from the IRF-1 knock-out mice. According to this study, IRF-1 role in resistance to tissue necrosis outweighs its impact on MHC molecules induction on graft endothelium. They attributed beneficial effects of IRF-1 to COX-2 upregulation which results in producing prostaglandin E2, vasodilatation, improved blood circulation and less necrosis [9]. In fact, this study was the only one to describe a positive function for IRF-1 in transplantation outcome because further researches demonstrated its unfavorable effects. For instance, Wang et al. compared two groups of IRF-1(−/−) and IRF-1(+/+) mice in response to ischemia, and found prominent inflammation in latter group which led to acute kidney injury (AKI). Besides, IRF-1 gene expression was shown to be elevated early after ischemia especially in proximal tubular cells. They concluded that IRF-1 is upregulated in tubules due to the reactive oxygen species produced during ischemia/reperfusion period and activates proinflammatory cytokines and chemokines expression whereby alloreactivity is triggered [10]. In A mice model of allogenic hematopoietic stem cell transplantation (HSCT), expression of genes involved in graft versus host disease (GVHD) has been evaluated in skin lesions and IFN-inducible genes including IRF-1 appeared to be among significantly upregulated genes [11]. Later, another animal study about GVHD confirmed previous findings by reporting IRF-1 overexpression in GVHD target organs [12]. Therefore, IRF-1 seems to play a role in GVHD development probably due to its involvement in T cells activation and inflammatory responses signaling. Since ischemia reperfusion injury (IRI) induces inflammatory responses in allograft and provides the initial encounter between allograft antigens and recipient's immune system, preventing its occurrence is one of the main challenges in transplantation. For this reason, every single molecule implicated in IRI initiation and/or progression is of interest in this area. Liver transplant is the most studied organ in term 2
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also markedly reduced IRI [17]. Nabavizadeh et al. studying 46 chronic HBV-infected patients who underwent liver transplantation demonstrated a significant elevation of IRF-1 gene expression during the first week of transplantation in rejecting group compared to the stable recipients [18]; however, Zhang et al. evaluated 127 hepatocellular carcinoma liver transplant cases and observed a positive significant correlation between IRF-1 expression levels and recurrence free survival after transplantation, here IRF-1 seems to have protective effect against hepatocellular carcinoma which outweighs its negative impact on transplantation [19]. There is some evidence for zinc supplements regulatory effect on lymphocytes, as it has been shown that when added to mixed lymphocyte reaction (MLR) environment, causes CD4 + CD25 + Foxp3+ and CD4 + CD25 + CTLA-4+ regulatory T cells induction; one of the underlying molecules responsible for this effect was IRF-1 which showed considerable downregulation subsequent to zinc supplementation [20]. Since Treg cells expansion and activation are in favor of allograft tolerance, this finding could be applied in transplantation to suppress IRF-1 and promote Tregs. In an animal model of islet cells transplantation, Solomon et al. could promote allograft survival by SOCS-1 (Suppressor of Cytokine Signaling-1) gene overexpression in transplanted cells. Later they found a significant correlation between protection against cytokine-induced cytotoxicity and inhibition of transcription factor IRF-1; therefore, it was suggested that SOCS-1 protection against islet allograft rejection could be attributed at least partly to the IRF-1 suppression [21].
IRF7 on the first day in rejecting group (20 patients) compared to the non-rejecting recipients which declined on the day 4 and upregulated again on seventh day, although it was not significant in case of IRF-3 [25]. 2.4. IRF-4 IRF-4 has recently gained a special interest in transplantation. This transcription factors implication in naϊve CD4+ T cells differentiation into Th2, Th9, Th17 and T follicular helper cells has already been shown; in fact, IRF-4 cooperates with different transcription factors including basic leucine zipper transcription factor ATF-like (BATF), NFAT, PU.1, SMAD2/3, ROR-γt, BCL-6, B-lymphocyte-induced maturation protein 1 (BLIMP1) and FOXP3 for T effector as well as eTreg cells induction [26]. IRF-4 significance in differentiation and activation of a wide range of T cells proposes it as a probable candidate for clinical interventions and therapeutic goals. One such intervention has demonstrated that IRF-4 inhibition by IRF-4 siRNA could promote liver allograft survival; as IRF-4-siRNA-treated mice displayed lower levels of TNF-α, IL-6 and IFN-γ, and higher amounts of anti-inflammatory cytokine IL-10 than control group. Furthermore, M2 macrophage differentiation enhances and acute rejection scores decreased significantly following IRF-4 inhibition [27]. Another animal study on liver transplantation found that Tacrolimus which is applied to control acute rejection episodes exerts its immunosuppressive effect by down-regulating IRF-4, NFAT, Foxp3 and RORγt transcription factors, all involved in T cells function [28]. Recently Wu and colleagues found that IRF-4 is required for mice heart transplant rejection. They showed that IRF-4 inhibits Helios and PD-1 genes expression which are critical for immunoregulation; therefore, blocking IRF-4 would result in PD-1 and Helios overexpression and consequently better allograft acceptance. Accordingly, they generated Irf4fl/fl Cd4-Cre mice and transplanted them by hearts from BALB/c donors. Allograft survival in IRF4 deficient mice was considerably improved comparing to the wild type recipients. This study demonstrated that T CD4+ cells are the main targets of suppression by IRF-4 deletion. Of note, T cells dysfunction showed to be irreversible after 30 days, the finding which proposes IRF-4 transcription factor as an appealing target to inhibit in transplant maintenance [3].
2.2. IRF-2 IRF-2 is another member of IRF family which competes with IRF1 for DNA binding sites of target genes and acts as a competitive inhibitor for it; therefore, IRF-2 is supposed to promote allograft survival by blocking harmful effects of IRF-1. In this regard, Klune et al. demonstrated that adenoviral transduction of IRF-2 gene into C57BL/6 mice results in IRF-2 overexpression in liver tissue and transplantation from these mice to wild type (WT) is protected against ischemia reperfusion injury when compared to the WT to WT. This finding was attributed to proinflammatory genes (e.g. IL-12, IFN-β and iNOS) downregulation in transgenic mice. Moreover, transplantation from IRF-2 heterozygote (IRF-2+/−) mice revealed to cause more tissue injuries following warm ischemia than normal mice (IRF-2+/+); so they suggested a protective role against IRI for IRF-2 in liver transplantation [22]. IRF-2 has also been studied in hematopoietic stem cell transplantation; contrary to IRF-1 which is thought to induce stem cells excessive proliferation and exhaustion, IRF-2 accounts for self-renewal and multi lineage differentiation capacity of these cells. HSCT from IRF-2 negative mice failed to function properly and displayed insufficient granulocytes reconstitution. They concluded that IRF2 is essential for preserving proper immunophenotypic combination of stem cells in bone marrow [23].
2.5. IRF-5 IRF-5 is considered to activate pro-inflammatory cytokines genes. It is also implicated in TLR4 signaling cascade, T lymphocytes activation, B-cell maturity and antibody production. This transcription factor has is involved in antiviral responses, tumor immunity and certain autoimmune diseases [29,30]. Although IRF-5 role in transplantation has not yet been thoroughly investigated, genomic study of 289 liver allograft recipients has shown significantly higher risk of acute rejection in IRF-5 rs3757385 G/G homozygote individuals. Since mentioned SNP is located in the promoter region, it could be assumed to affect IRF-5 gene expression level; however, the authors indicated that gene expression study in PBMCs of three main IRF-5 SNPs (rs3757385, rs752637 and rs11761199) carriers displayed no significant difference [31].
2.3. IRF-3 Martin-Antonio et al. studying 249 AML patients submitted to HLAidentical sibling HSCT found that donors carrying GG gene variant in rs7251 of IRF-3 gene induce lower grades of GVHD and more relapse rates because this variant is associated with lower IFN-γ production, decreased lymphocyte proliferation after DCs stimulation, and lower cytotoxic activity of mature NK cells. It seems that this variant codes for a missense change which could alter the interaction of IRF3 with the downstream genes in inflammatory pathways. They recommended GG donors for non-malignant indications in order to prevent from severe GVHD [24]. Janfeshan and colleagues evaluated IRF-3 and IRF-7 genes expression in peripheral mononuclear cells (PBMCs) of 46 patients with chronic HBV infection on the days 1, 4, and 7 after liver transplantation. They observed a considerable increase in mRNA level of IRF3 and
2.6. IRF-7 Given that IRF-7 is one of the main regulators of type I interferons, Minisini et al. investigated the correlation between IRF-7A mRNA expression level and acute rejection episodes in 71 liver transplant recipients two months and one year post-transplant. They demonstrated that acute rejection is accompanied by higher levels of IRF-7A expression in graft tissue and suggested a predictive value for IRF-7 in clinic [32]. This finding is supported by abovementioned study of Janfeshan et al. who also reported IRF-7 expression elevation during liver allograft acute rejection episodes [25]. In addition, a case report about a 3
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Table 1 Interferon regulatory factors implication in transplantation. IRF subtype
Organ
Effect
IRF-1
Kidney hematopoietic stem cell Liver
COX-2 ↑, prostaglandin E2↑,vasodilatation (6), proinflammatory cytokines and chemokines↑(7) up regulation in skin lesions of GVHD (8), overexpression in GVHD target organs (9) TNF-α, IL-6, ICAM-1 and iNOS↑ (10), IFN-β, IFN-δ, IL-12, and iNOS↑(11), IL-15 and IL-15Rα mRNA expression↑, NK, NKT, and CD8+ T cells↑ (12), TRAIL, DR5, Fas, FasL and IFN-γ expression↑, caspase-8 activity↑ (13), IL-6 and TNF-α secretion from plasmacytoid DCs↑ (14), Overexpression in graft rejection (15), CD4 + CD25 + Foxp3+ and CD4 + CD25 + CTLA-4+ T cells↓ (17) Inhibition results in better survival (18) IL-12, IFN-β and iNOS↓(19) lineage differentiation and reconstitution (20) GG gene variant of rs7251 accompanied by lower grades of GVHD (21) Upregulated in rejection (22) IL-10↓,M2 macrophage differentiation↓, TNF-α, IL-6 and IFN-γ↓, acute rejection↑,inhibition results in better survival (24), downregulation by Tacrolimus (25) PD-1 and Helios genes expression↓, Acute rejection↑(26) GG variant of rs3757385 accompanied by acute rejection (27) _ Upregulated in rejection (22), Acute rejection↑ (28) Lupus recurrence after HSCT (29) _ Ischemia reperfusion injury ↑ (30) Overexpression in IRI (31)
IRF-2 IRF-3 IRF-4 IRF-5 IRF-6 IRF-7 IRF-8 IRF-9
Islet cells Liver hematopoietic stem cell hematopoietic stem cell Liver Liver Heart Liver _ Liver hematopoietic stem cell _ Heart Liver
GVHD: graft versus host disease, HSCT: hematopoietic stem cell transplantation IRI: ischemia reperfusion study.
molecules, it would not be so easy to inhibit their effect in vivo; however, there is evidence of some natural viral products which inhibit certain IRFs selectively in order to regulate immune responses in favor of viruses. For instance, Hepatitis C Virus Serine Protease [36], human respiratory syncytial virus NS1 protein [37], Paramyxovirus V Protein [38], Ebola Virus VP35 Protein [39] and IRF-3 homologue vIRF-3 [40] have been shown to inhibit IRF-3;moreover, chromosome 6 ORF 106 (C6orf106) an evolutionarily conserved inhibitor of antiviral response has recently been described to inhibit IRF-3 [41]. In addition, Trametinib, a MEK1/2 inhibitor, has been applied successfully for IRF-4 inhibition in animal model of heart transplant [3]. In summary, although our current information about interferon regulatory factors' impact on transplantation is insufficient and it might be too soon to discuss on their manipulation in clinic, these transcription factors could be considered as promising subjects for future experiments.
refractory lupus patient who underwent autologous hematopoietic stem cell transplantation showed that IRF-7 protein expression is correlated with elevated levels of IFN-α and IFN-β, as well as lupus disease recurrence and activity after transplantation [33]. Therefore, IRF-7 expression in tissue might be associated with worse graft outcomes. 2.7. IRF-9 There is no evidence of IRF-9 direct implication in transplantation; nonetheless, it has been studied in ischemia reperfusion injury of heart and liver [34,35]. Zhang et al. evaluated IRF-9 expression in heart ischemia and observed increased levels of IRF-9 in human and mouse heart tissue after IRI. Ablation of IRF9 protected the heart against inflammation, cardiomyocyte death, and loss of function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF-9 exacerbated myocardial injury [35]. In mice model of liver warm ischemia, injuries were aggravated in IRF-9-overexpressing animals whereas, IRF-9 deficiency markedly reduced immune cells infiltration, inflammatory cytokines level, and hepatocyte apoptosis [34]. According to the fact that protecting allograft from ischemia reperfusion injury is one of the main goals in transplantation, IRF-9 inhibition might be suggested as a probable therapeutic idea.
Declarations of interest None. Funding None.
3. Conclusion
Ethical approval
Taken together, it seems that interferon regulatory factors affect transplantation outcome by inducing and augmenting harmful inflammatory responses. IRF-1 and 9 are profoundly involved in pathogenesis of ischemia reperfusion injury whereas IRF-2 seems to play a protective role. Two SNPs of IRF-3 and 5 genes have been recognized to be associated positively and negatively with graft survival respectively. IRF-4 is considered as a principal transcription factor in T cells differentiation and function; it inhibits regulatory molecules like PD-1 and Helios; therefore, IRF-4 could be a potential target to be studies in developing future immunosuppressive drugs. Finally, IRF-7 is a potent inducer of inflammation so its elevated expression could be predictive of acute rejection (Table 1). Regarding IRFs significant impact on immune responses, further studied are required to define their precise influence on transplant outcome. Besides, it is essential to find safe, specific and feasible ways to manipulate them in order to prolong graft survival. According to the fact that there is no approved chemical inhibitory substance for these
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Transplant Immunology journal homepage: www.elsevier.com/locate/trim
Review
Interferon regulatory factors: Where to stand in transplantation Sara Assadiasla, , Abbas Shahib, Saeedeh Salehib, Shima Afzalib, Aliakbar Amirzargara,b ⁎
a b
Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
ARTICLE INFO
ABSTRACT
Keywords: Interferon regulatory factor Transplantation Rejection Ischemia reperfusion injury
Interferon regulatory factors (IRFs) are implicated in regulating inflammatory responses to pathogens and alloantigens. Since transplantation is usually accompanied by ischemia reperfusion injury (IRI), acute and chronic rejections, as well as immunodeficiency due to immunosuppressive drugs, IRFs seem to play a considerable role in allograft outcome. For instance, IRF-1 has been shown to be involved in pathogenesis of IRI; however, IRF-2 exhibits an opposite function. Some IRF-3 and 5 SNPs are associated with better or worse graft survival rates. Of note, IRF-4 inhibition has resulted in improved transplant outcomes. Herein we review available studies about IRFs influence on various stages of transplantation.
1. Introduction Solid organ and stem cell transplantation have recently been considered as the main modalities in treating end stage organ damage and various life-threatening hematologic disorders. However, despite all surgical and pharmacological advancements, recipients' survival rate and quality of life are not satisfying enough. In fact, adverse effects of immunosuppressive (IS) drugs such as hyperglycemia, dyslipidemia, osteoporosis,gastrointestinal complications, along with the increased risk of infection, lymphoproliferative disorders and skin malignancies turn them into a secondary challenge after transplantation [1]. Therefore, many efforts have been made to relieve the patients from lifelong medications or replace currently used drugs with those of less toxicity. Among all studied ideas, specific manipulation of immune system for inhibiting exaggerated responses to alloantigens has been considered as the most appropriate option. In order to achieve this goal there is no way but identifying functional details of every single immune component involved in graft rejection or tolerance [2]. In this regard, recently some encouraging findings have been published about IRF-4 inhibition in transplantation and as a result considerable promotion in cardiac allograft survival, which brought the idea of targeting these molecules to regulate immune responses specifically and efficiently with fewer metabolic side effects [3,4]; therefore, we decided to review all available studies about different IRFs correlation with transplantation. Interestingly, there were remarkable findings which deserved to be shared in order to provoke further investigations for defining whether IRFs could be eligible candidates for future therapeutic strategies or not.
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Interferon regulatory factors (IRFs) implication in pathogenesis of autoimmunity and malignancies has already been investigated and some members of this family have been shown to be directly contributed to certain disease, for instance IRF6 expression has a negative correlation with breast cancer invasiveness and several IRF polymorphisms which increase their expression have been recognized to be involved in Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD) and Systemic lupus erythematosus (SLE) pathogenesis [5,6]. Regarding interferon regulatory factors profound implication in immune cells development and activation in addition to their prominent association with autoimmune diseases, it is time to understand their function in transplantation. 2. Interferon regulatory factors The family of IRF transcription factors includes nine members of IRF1–9, all sharing a common DNA binding domain (DBD) structure. DBD consists of approximately 115 amino acids composed of several five-tryptophan sequences which form a helix-turn-helix structure involved in binding to INF-stimulated response element (ISRE) on target DNA. Contrary to similar DBD site, the carboxy-terminal region is different between IRFs for instance, there is an IRF-associated domain 2 (IAD2) in variable part of IRF-1 and 2, but the rest of IRFs contain IAD1 (Fig. 1) [5]. IRFs were first recognized as type 1 interferon (IFN) genes transcription factors but later their involvement in producing IFN-γ, oncogenesis, metabolism and immune cells development was demonstrated. They are also involved in pathogen recognition receptors (PRR)
Corresponding author at: Molecular immunology research center, Children's Medical Center, 62 Qarib St., Keshavarz Blvd., Tehran 14194, Iran. E-mail address: [email protected] (S. Assadiasl).
https://doi.org/10.1016/j.trim.2018.10.001 Received 14 August 2018; Received in revised form 10 October 2018; Accepted 12 October 2018 0966-3274/ © 2018 Elsevier B.V. All rights reserved.
Please cite this article as: Assadiasl, S., Transplant Immunology, https://doi.org/10.1016/j.trim.2018.10.001
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Fig. 1. Schematic illustration of different interferon regulatory factor (IRF) molecules structure.
of IRF-1 contribution to the IRI. Tsung et al. studied a group of mice which were subjected to hepatic ischemia for 60 min; they demonstrated that IRF-1 knockout mice were resistant to IRI as compared to the control mice which displayed significantly higher expression levels of TNF-α, IL-6 and ICAM-1, in addition to the elevated amounts of inducible nitric oxide synthase (iNOS). Besides, adenoviral delivery of IRF-1 gene into the knockout mice resulted in considerable tissue injury following ischemia induction. So they suggested a principal role for IRF1 in IRI [13]. Later, Kim et al. injected IRF-1-expressing adenovirus (AdIRF-1) and control gene vector (Adnull) to the two groups of donor rats 4 days prior to the harvesting, and then transplanted transduced livers to the normal rats. Two days later, recipients from AdIRF-1 rats showed elevated levels of liver enzymes along with increased expression of IFN-β, IFN-δ, IL-12, and iNOS. Moreover, overexpression of IRF1 resulted in augmented activation of JNK/MAP kinase signaling pathway in addition to enhanced hepatocellular apoptosis and necrosis [14]. Consistent with these results, Yokota and colleagues demonstrated better liver transplant outcomes from IRF-1 knockout mice. IL15 and IL-15Rα mRNA expression, as well as NK, NKT, and CD8+ T cells population were reduced in allograft. Furthermore, they evaluated human hepatocytes before and after transplantation and reported IRF-1 overexpression following ischemia in these cells; IL-15 and IL-15Rα expression showed to be upregulated in an IRF-1–dependent manner. Moreover, after human IRF-1 gene silencing ischemia-related inflammation was resolved, the effect which was demonstrated to be reversible by IL-15/IL-15Rα complexes induction, so they suggested IL15 and IL-15Rα overexpression due to IRF-1 upregulation as an underlying mechanism for ischemia reperfusion injury [15]. A similar study showed that liver transplantation from IRF-1 knockout mice to wild type is accompanied by significantly lower levels of TRAIL (TNFrelated apoptosis-inducing ligand), DR5 (Death receptor5), Fas, FasL and IFN-γ expression in allograft comparing to the control model (WT to WT). Moreover, caspase-8 activity was inhibited in KO to WT model. These findings provide more evidence for IRF-1 contribution to the post-transplant insults [16]. Additionally, it has been demonstrated that maturation of liver plasmacytoid dendritic cells (pDC) is augmented by ischemia reperfusion. These cells promote IRF-1 expression through IFN-α secretion which consequently provokes IL-6 and TNF-α production together with hepatocytes apoptosis. To confirm these findings, they showed that applying anti-IFN-α mAb 30 min before ischemia resulted in IRF-1 inhibition and protected the liver tissue from IRI. In vivo depletion of pDCs using anti-mPDCA-1 pure-functional grade mAb
signaling to chromatin for immune cells activation. Although most IRFs are mainly expressed in immune cells and play a significant role in T, B, NK, as well as dendritic cells maturation and function, some members like IRF- 3, 4, 5, 7 and 8 have been found to express in kidney, liver and heart tissue participating in pathogenesis of metabolic disorders [7,8]. 2.1. IRF-1 One of the first studies about IRF-1 impact on transplant outcome was performed by Afrouzian et al. who observed better survival rates in mice receiving wild type renal allograft comparing to the group which were transplanted from the IRF-1 knock-out mice. According to this study, IRF-1 role in resistance to tissue necrosis outweighs its impact on MHC molecules induction on graft endothelium. They attributed beneficial effects of IRF-1 to COX-2 upregulation which results in producing prostaglandin E2, vasodilatation, improved blood circulation and less necrosis [9]. In fact, this study was the only one to describe a positive function for IRF-1 in transplantation outcome because further researches demonstrated its unfavorable effects. For instance, Wang et al. compared two groups of IRF-1(−/−) and IRF-1(+/+) mice in response to ischemia, and found prominent inflammation in latter group which led to acute kidney injury (AKI). Besides, IRF-1 gene expression was shown to be elevated early after ischemia especially in proximal tubular cells. They concluded that IRF-1 is upregulated in tubules due to the reactive oxygen species produced during ischemia/reperfusion period and activates proinflammatory cytokines and chemokines expression whereby alloreactivity is triggered [10]. In A mice model of allogenic hematopoietic stem cell transplantation (HSCT), expression of genes involved in graft versus host disease (GVHD) has been evaluated in skin lesions and IFN-inducible genes including IRF-1 appeared to be among significantly upregulated genes [11]. Later, another animal study about GVHD confirmed previous findings by reporting IRF-1 overexpression in GVHD target organs [12]. Therefore, IRF-1 seems to play a role in GVHD development probably due to its involvement in T cells activation and inflammatory responses signaling. Since ischemia reperfusion injury (IRI) induces inflammatory responses in allograft and provides the initial encounter between allograft antigens and recipient's immune system, preventing its occurrence is one of the main challenges in transplantation. For this reason, every single molecule implicated in IRI initiation and/or progression is of interest in this area. Liver transplant is the most studied organ in term 2
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also markedly reduced IRI [17]. Nabavizadeh et al. studying 46 chronic HBV-infected patients who underwent liver transplantation demonstrated a significant elevation of IRF-1 gene expression during the first week of transplantation in rejecting group compared to the stable recipients [18]; however, Zhang et al. evaluated 127 hepatocellular carcinoma liver transplant cases and observed a positive significant correlation between IRF-1 expression levels and recurrence free survival after transplantation, here IRF-1 seems to have protective effect against hepatocellular carcinoma which outweighs its negative impact on transplantation [19]. There is some evidence for zinc supplements regulatory effect on lymphocytes, as it has been shown that when added to mixed lymphocyte reaction (MLR) environment, causes CD4 + CD25 + Foxp3+ and CD4 + CD25 + CTLA-4+ regulatory T cells induction; one of the underlying molecules responsible for this effect was IRF-1 which showed considerable downregulation subsequent to zinc supplementation [20]. Since Treg cells expansion and activation are in favor of allograft tolerance, this finding could be applied in transplantation to suppress IRF-1 and promote Tregs. In an animal model of islet cells transplantation, Solomon et al. could promote allograft survival by SOCS-1 (Suppressor of Cytokine Signaling-1) gene overexpression in transplanted cells. Later they found a significant correlation between protection against cytokine-induced cytotoxicity and inhibition of transcription factor IRF-1; therefore, it was suggested that SOCS-1 protection against islet allograft rejection could be attributed at least partly to the IRF-1 suppression [21].
IRF7 on the first day in rejecting group (20 patients) compared to the non-rejecting recipients which declined on the day 4 and upregulated again on seventh day, although it was not significant in case of IRF-3 [25]. 2.4. IRF-4 IRF-4 has recently gained a special interest in transplantation. This transcription factors implication in naϊve CD4+ T cells differentiation into Th2, Th9, Th17 and T follicular helper cells has already been shown; in fact, IRF-4 cooperates with different transcription factors including basic leucine zipper transcription factor ATF-like (BATF), NFAT, PU.1, SMAD2/3, ROR-γt, BCL-6, B-lymphocyte-induced maturation protein 1 (BLIMP1) and FOXP3 for T effector as well as eTreg cells induction [26]. IRF-4 significance in differentiation and activation of a wide range of T cells proposes it as a probable candidate for clinical interventions and therapeutic goals. One such intervention has demonstrated that IRF-4 inhibition by IRF-4 siRNA could promote liver allograft survival; as IRF-4-siRNA-treated mice displayed lower levels of TNF-α, IL-6 and IFN-γ, and higher amounts of anti-inflammatory cytokine IL-10 than control group. Furthermore, M2 macrophage differentiation enhances and acute rejection scores decreased significantly following IRF-4 inhibition [27]. Another animal study on liver transplantation found that Tacrolimus which is applied to control acute rejection episodes exerts its immunosuppressive effect by down-regulating IRF-4, NFAT, Foxp3 and RORγt transcription factors, all involved in T cells function [28]. Recently Wu and colleagues found that IRF-4 is required for mice heart transplant rejection. They showed that IRF-4 inhibits Helios and PD-1 genes expression which are critical for immunoregulation; therefore, blocking IRF-4 would result in PD-1 and Helios overexpression and consequently better allograft acceptance. Accordingly, they generated Irf4fl/fl Cd4-Cre mice and transplanted them by hearts from BALB/c donors. Allograft survival in IRF4 deficient mice was considerably improved comparing to the wild type recipients. This study demonstrated that T CD4+ cells are the main targets of suppression by IRF-4 deletion. Of note, T cells dysfunction showed to be irreversible after 30 days, the finding which proposes IRF-4 transcription factor as an appealing target to inhibit in transplant maintenance [3].
2.2. IRF-2 IRF-2 is another member of IRF family which competes with IRF1 for DNA binding sites of target genes and acts as a competitive inhibitor for it; therefore, IRF-2 is supposed to promote allograft survival by blocking harmful effects of IRF-1. In this regard, Klune et al. demonstrated that adenoviral transduction of IRF-2 gene into C57BL/6 mice results in IRF-2 overexpression in liver tissue and transplantation from these mice to wild type (WT) is protected against ischemia reperfusion injury when compared to the WT to WT. This finding was attributed to proinflammatory genes (e.g. IL-12, IFN-β and iNOS) downregulation in transgenic mice. Moreover, transplantation from IRF-2 heterozygote (IRF-2+/−) mice revealed to cause more tissue injuries following warm ischemia than normal mice (IRF-2+/+); so they suggested a protective role against IRI for IRF-2 in liver transplantation [22]. IRF-2 has also been studied in hematopoietic stem cell transplantation; contrary to IRF-1 which is thought to induce stem cells excessive proliferation and exhaustion, IRF-2 accounts for self-renewal and multi lineage differentiation capacity of these cells. HSCT from IRF-2 negative mice failed to function properly and displayed insufficient granulocytes reconstitution. They concluded that IRF2 is essential for preserving proper immunophenotypic combination of stem cells in bone marrow [23].
2.5. IRF-5 IRF-5 is considered to activate pro-inflammatory cytokines genes. It is also implicated in TLR4 signaling cascade, T lymphocytes activation, B-cell maturity and antibody production. This transcription factor has is involved in antiviral responses, tumor immunity and certain autoimmune diseases [29,30]. Although IRF-5 role in transplantation has not yet been thoroughly investigated, genomic study of 289 liver allograft recipients has shown significantly higher risk of acute rejection in IRF-5 rs3757385 G/G homozygote individuals. Since mentioned SNP is located in the promoter region, it could be assumed to affect IRF-5 gene expression level; however, the authors indicated that gene expression study in PBMCs of three main IRF-5 SNPs (rs3757385, rs752637 and rs11761199) carriers displayed no significant difference [31].
2.3. IRF-3 Martin-Antonio et al. studying 249 AML patients submitted to HLAidentical sibling HSCT found that donors carrying GG gene variant in rs7251 of IRF-3 gene induce lower grades of GVHD and more relapse rates because this variant is associated with lower IFN-γ production, decreased lymphocyte proliferation after DCs stimulation, and lower cytotoxic activity of mature NK cells. It seems that this variant codes for a missense change which could alter the interaction of IRF3 with the downstream genes in inflammatory pathways. They recommended GG donors for non-malignant indications in order to prevent from severe GVHD [24]. Janfeshan and colleagues evaluated IRF-3 and IRF-7 genes expression in peripheral mononuclear cells (PBMCs) of 46 patients with chronic HBV infection on the days 1, 4, and 7 after liver transplantation. They observed a considerable increase in mRNA level of IRF3 and
2.6. IRF-7 Given that IRF-7 is one of the main regulators of type I interferons, Minisini et al. investigated the correlation between IRF-7A mRNA expression level and acute rejection episodes in 71 liver transplant recipients two months and one year post-transplant. They demonstrated that acute rejection is accompanied by higher levels of IRF-7A expression in graft tissue and suggested a predictive value for IRF-7 in clinic [32]. This finding is supported by abovementioned study of Janfeshan et al. who also reported IRF-7 expression elevation during liver allograft acute rejection episodes [25]. In addition, a case report about a 3
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Table 1 Interferon regulatory factors implication in transplantation. IRF subtype
Organ
Effect
IRF-1
Kidney hematopoietic stem cell Liver
COX-2 ↑, prostaglandin E2↑,vasodilatation (6), proinflammatory cytokines and chemokines↑(7) up regulation in skin lesions of GVHD (8), overexpression in GVHD target organs (9) TNF-α, IL-6, ICAM-1 and iNOS↑ (10), IFN-β, IFN-δ, IL-12, and iNOS↑(11), IL-15 and IL-15Rα mRNA expression↑, NK, NKT, and CD8+ T cells↑ (12), TRAIL, DR5, Fas, FasL and IFN-γ expression↑, caspase-8 activity↑ (13), IL-6 and TNF-α secretion from plasmacytoid DCs↑ (14), Overexpression in graft rejection (15), CD4 + CD25 + Foxp3+ and CD4 + CD25 + CTLA-4+ T cells↓ (17) Inhibition results in better survival (18) IL-12, IFN-β and iNOS↓(19) lineage differentiation and reconstitution (20) GG gene variant of rs7251 accompanied by lower grades of GVHD (21) Upregulated in rejection (22) IL-10↓,M2 macrophage differentiation↓, TNF-α, IL-6 and IFN-γ↓, acute rejection↑,inhibition results in better survival (24), downregulation by Tacrolimus (25) PD-1 and Helios genes expression↓, Acute rejection↑(26) GG variant of rs3757385 accompanied by acute rejection (27) _ Upregulated in rejection (22), Acute rejection↑ (28) Lupus recurrence after HSCT (29) _ Ischemia reperfusion injury ↑ (30) Overexpression in IRI (31)
IRF-2 IRF-3 IRF-4 IRF-5 IRF-6 IRF-7 IRF-8 IRF-9
Islet cells Liver hematopoietic stem cell hematopoietic stem cell Liver Liver Heart Liver _ Liver hematopoietic stem cell _ Heart Liver
GVHD: graft versus host disease, HSCT: hematopoietic stem cell transplantation IRI: ischemia reperfusion study.
molecules, it would not be so easy to inhibit their effect in vivo; however, there is evidence of some natural viral products which inhibit certain IRFs selectively in order to regulate immune responses in favor of viruses. For instance, Hepatitis C Virus Serine Protease [36], human respiratory syncytial virus NS1 protein [37], Paramyxovirus V Protein [38], Ebola Virus VP35 Protein [39] and IRF-3 homologue vIRF-3 [40] have been shown to inhibit IRF-3;moreover, chromosome 6 ORF 106 (C6orf106) an evolutionarily conserved inhibitor of antiviral response has recently been described to inhibit IRF-3 [41]. In addition, Trametinib, a MEK1/2 inhibitor, has been applied successfully for IRF-4 inhibition in animal model of heart transplant [3]. In summary, although our current information about interferon regulatory factors' impact on transplantation is insufficient and it might be too soon to discuss on their manipulation in clinic, these transcription factors could be considered as promising subjects for future experiments.
refractory lupus patient who underwent autologous hematopoietic stem cell transplantation showed that IRF-7 protein expression is correlated with elevated levels of IFN-α and IFN-β, as well as lupus disease recurrence and activity after transplantation [33]. Therefore, IRF-7 expression in tissue might be associated with worse graft outcomes. 2.7. IRF-9 There is no evidence of IRF-9 direct implication in transplantation; nonetheless, it has been studied in ischemia reperfusion injury of heart and liver [34,35]. Zhang et al. evaluated IRF-9 expression in heart ischemia and observed increased levels of IRF-9 in human and mouse heart tissue after IRI. Ablation of IRF9 protected the heart against inflammation, cardiomyocyte death, and loss of function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF-9 exacerbated myocardial injury [35]. In mice model of liver warm ischemia, injuries were aggravated in IRF-9-overexpressing animals whereas, IRF-9 deficiency markedly reduced immune cells infiltration, inflammatory cytokines level, and hepatocyte apoptosis [34]. According to the fact that protecting allograft from ischemia reperfusion injury is one of the main goals in transplantation, IRF-9 inhibition might be suggested as a probable therapeutic idea.
Declarations of interest None. Funding None.
3. Conclusion
Ethical approval
Taken together, it seems that interferon regulatory factors affect transplantation outcome by inducing and augmenting harmful inflammatory responses. IRF-1 and 9 are profoundly involved in pathogenesis of ischemia reperfusion injury whereas IRF-2 seems to play a protective role. Two SNPs of IRF-3 and 5 genes have been recognized to be associated positively and negatively with graft survival respectively. IRF-4 is considered as a principal transcription factor in T cells differentiation and function; it inhibits regulatory molecules like PD-1 and Helios; therefore, IRF-4 could be a potential target to be studies in developing future immunosuppressive drugs. Finally, IRF-7 is a potent inducer of inflammation so its elevated expression could be predictive of acute rejection (Table 1). Regarding IRFs significant impact on immune responses, further studied are required to define their precise influence on transplant outcome. Besides, it is essential to find safe, specific and feasible ways to manipulate them in order to prolong graft survival. According to the fact that there is no approved chemical inhibitory substance for these
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