Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19.

Interferon Regulatory Factor 5 (IRF5) Gene Haplotypes Are Associated with Premature Coronary Artery Disease Association of the IRF5 Polymorphisms with Cardiometabolic Parameters the Genetics of Atherosclerotic Disease (GEA) Mexican Study

Interferon regulatory factor 5 (IRF5) has an important role in the inflammatory process, a fundamental component of coronary artery disease (CAD). Thus, the objective of this study was to evaluate the association of IRF5 polymorphisms with the development of premature CAD (pCAD) and cardiometabolic parameters. IRF5 polymorphisms (rs1874330, rs3778754, rs3757386, rs3757385, rs3807134, rs3807135, and rs6968563) were determined in 1116 pCAD patients and 1003 controls. Polymorphism distribution was similar in patients and controls; however, the haplotype analysis showed five haplotypes with a different distribution. TGCGTCT (OR (odds ratio) = 1.248, p = 0005) and TCTGCCT (OR = 10.73, p < 0.0001) were associated with a high risk, whereas TCCGTCT (OR = 0.155, p < 0.0001), CGCTTTT (OR = 0.108, p < 0.0001), and TCCGCCT (OR = 0.014, p < 0.0001) were associated with a low risk of pCAD. Associations with aspartate aminotransferase, hypertriglyceridemia, magnesium deficiency, triglycerides/HDL-C index, LDL-C, and adiponectin levels were observed in pCAD patients. In controls, associations with hypoalphalipoproteinemia, non-HDL-C, apolipoprotein B, hyperuricemia, TNF-α, IL-6, IL-15, valvular calcification, and subclinical hypothyroidism were observed. In summary, five haplotypes were associated with pCAD, two with high risk and three with low risk. Some IRF5 polymorphisms were associated with cardiometabolic parameters in pCAD patients and control.

Interferon Regulatory Factor 5 siRNA-Loaded Folate-Modified Cationic Liposomes for Acute Lung Injury Therapy

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an overwhelming pulmonary inflammation with limited clinical treatment strategies. Interferon regulatory factor 5 (IRF5) is a crucial regulator of inflammation factors, which can be upregulated under an inflammatory state and related to the efferocytosis of macrophages. Herein, IRF5 was knockdown by small interfering RNA (siIRF5) to promote the anti-inflammatory effect of macrophages. Macrophage-targeting cationic liposome modified by folate (FA-LP) was developed to deliver siIRF5 (FA-LP/siIRF5). Liposomes were characterized for their particle size, zeta potential, protein adsorption and hemolysis of red blood cells. The amount of IRF5 mRNA and the expression of IRF5 were measured using quantitative reverse transcription PCR (RT-qPCR) and western blot, respectively. The phenotype and efferocytosis of macrophages and the regulatory pathway of efferocytosis and biodistribution of liposomes in the ALI mice model were investigated. Data revealed that FA-LP/siIRF5 could obviously downregulate the expression of IRF5 in macrophages, skewing the polarization of macrophages to M2 phenotype (anti-inflammatory state) and thus improving their efferocytosis. Moreover, regulation of efferocytosis of macrophages by siIRF5 is related to the NF- B pathway. The in vivo biodistribution of FA-LP exhibited higher accumulation in the inflammatory lungs, suggesting that FA-LP could be considered as a promising gene delivery system and FA-LP/siIRF5 is an alternative strategy for the treatment of ALI/ARDS. To the best of our knowledge, this is the first study reporting that siIRF5 can be used for the treatment of ALI/ARDS.

Identification and characterisation of single nucleotide polymorphisms in interferon regulatory factor-5 gene of Nigerian local chickens

The interferon regulatory factor gene family encodes transcription factors with multiple biological functions, which include reproduction, cell differentiation and immunity. Interferon regulatory factor-5 (IRF-5) gene is involved in immune defence against virus, stress response, activation of type I interferon genes, cell differentiation and growth. This experiment was conducted to identify and characterise single nucleotide polymorphisms in exons 3, 4, 5 and 7 of IRF-5 gene in Nigerian local chickens. Exons 3, 4, 5 and 7 of IRF-5 gene were amplified and sequenced. Single nucleotide polymorphisms (SNPs) present in exons 3, 4, 5 and 7 of IRF-5 gene were identified and analysed using Clustal W, DnaSp and SNAP2 software packages. Four SNPs, rs317511101, rs312902332, rs315149141 and rs739389464, were identified in exon 3 of IRF-5 gene in all the three genotypes. Exon 4 of the gene was conserved while three of the SNPs (rs736423928, 170C>T and rs740736761) identified in exon 7 were shared among the three genotypes. Linkage disequilibrium of 1.00 existed between rs317511101 and rs315149141 polymorphisms identified in exon 3 of normal feathered and frizzle feathered chickens. Mutation rs740736761 identified in exon 7 had the highest polymorphism information content obtainable for any biallelic marker. Most of the SNPs identified in exons 3, 5 and 7 were synonymous and singletons which could not be used for association study. The study concluded that only haplotypes in exons 3 and 7 of IRF-5 gene can be used in marker-assisted selection when improving Nigerian local chickens.

Relating Interferon Regulatory Factor 5 Rs2004640 Gene Polymorphism To Increased Risk Of Systemic Sclerosis In The Patients: Russian Federation Cohort

Background ― A number of studies confirmed a crucial role of type 1 interferon in pathophysiology of connective tissue diseases. Interferon regulatory factors (IRF) coordinate an expression of type 1 interferon, while interferon regulatory factor 5 (IRF5) gene was recently identified as causing predisposition to systemic lupus erythematosus and Sjögren syndrome. The objective of our study was to identify possible association of IRF5 rs2004640 (G/T) single nucleotide polymorphism with systemic sclerosis (SSc). Material and Methods―The study involved 236 individuals, including 105 patients with SSc diagnosis and 131 control individuals from Moscow region. The latter were healthy, unrelated to each other, their genders and ages were matched to those of SSc patients. Allele-specific real-time polymerase chain reaction (PCR) was used to study IFR5 rs2004640 polymorphism. Results ― We detected significantly higher percentage of IRF5 T-allele carriers in all patients (59.5%), those with diffuse cutaneous SSc (67.3%), patients with interstitial lung lesions (62.3%), and those with positive titers of anti-topoisomerase I antibodies (66.3%), compared with control group (46.2%). The odds ratios (OR) were: 1.71 (р=0.00), 2.40 (р=0.0004), 1.93 (р=0.002), and 2.30 (р=0.0008), correspondingly. Conclusion ― The replacement of nucleotide G by T in the IRF5 rs2004640 gene polymorphism was associated with a predisposition to SSc. Our data implied an existence of a novel SSc pathogenetic pathway associated with important role of type 1 interferon in pathophysiology of connective tissue diseases.

Interferon Regulatory Factor 5 Mediates Lipopolysaccharide-Induced Neuroinflammation

BackgroundActivated microglia play a vital role in neuroinflammation in the central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in the periphery, the role of which in the CNS remains elusive.MethodsLipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immunofluorescence and Western blot.ResultsLPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b-positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which were comparable to control group at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling.ConclusionsIRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.