Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09-2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype "T-A" containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15-0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Single nucleotide polymorphisms in cytokine genes and their association with primary Sjögren's syndrome in Saudi patients: A cross-sectional study.

OBJECTIVES: To determine the allelic frequencies and effects of genotypic variations in cytokine gene polymorphisms in a Saudi Arabian population. METHODS: This cross-sectional study involved 41 patients with Primary Sjögren's syndrome (pSS) and 71 healthy controls between October 2018 and May 2019. Single nucleotide polymorphisms genotyping was performed using the SEQUENOM MassARRAY® System, targeting nine polymorphisms in different cytokine genes. Chi-square tests were used to compare the patients and controls. RESULTS: The interleukin-1 beta (IL-1ß) rs1143627 CT (control, 52.7%; patients, 21.2%) and TT + CT (p= 0.003; p=0.033) genotypes were less frequent in patients with pSS than in healthy controls. The C allele in rs10488631 in the interferon regulatory factor 5 (IRF5) gene and the A allele in rs12583006 in the B-cell activating factor (BAFF) gene were associated with an increased risk of pSS development in the patient group. CONCLUSION: The CT genotype at -31 (rs1143627) in the IL-1ß gene was not associated with a high risk of pSS development in the Saudi population, in contrast to what has been verified in other ethnicities. However, the C allele in rs10488631 in IRF-5 and the A allele in rs12583006 in BAFF were associated.

Cross-reactivity between Mycobacterium avium subspecies paratuberculosis 4027 peptide and Human IRF5 may contribute to Multiple Sclerosis in Iranian patients.

Background: The etiology of Multiple sclerosis (MS) is complicated and can be affected by several environmental factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) infection in genetically predisposed individuals. The link between MAP and MS depends on host genetic and epigenetic aspects and population-based features that require further investigation. We aimed to study the possible role of MAP in triggering MS using molecular and serological methods. Materials and methods: This case-control study examined 200 blood samples (100 MS patients and 100 HCs) to search for the MAP-specific IS900 gene. In addition, ELISA was conducted to determine the humoral response against MAP_402718-32 and its human IRF5424-434 peptide homolog. Results: The frequency of MAP detection based on the molecular method in MS patients and HCs was 48 % and 13 %, respectively (p < 0.0001). The presence of antibodies against MAP_402718-32 and IRF5424-434 was 55 % and 65 % in MS patients versus 9 % and 7 % in HCs, respectively (p < 0.0001). A good correlation was observed between MAP_4027 and IRF5 antibodies (r = 0.5782, p < 0.0001), indicating that the same antibodies recognized common peptide epitopes. Conclusion: Our research revealed a significant association between MAP and MS, highlighting the possible role of MAP as an important infection trigger factor of MS. It is hypothesized that cross-reactivity between MAP4027 and IRF5 may dysregulate immune homeostasis.

IRF5-TNOP3 polymorphisms are associated with elite control of HIV infection: A retrospective study.

IRF5-TNPO3 polymorphisms have previously been related to immune response, and TNPO3 plays a role in human immunodeficiency virus (HIV)-1 infection after nuclear import. Therefore, we analyzed the genetic association between IRF5-TNPO3 polymorphisms and the HIV elite control in long-term nonprogressors (LTNPs). We performed a retrospective cohort study on 183 LTNPs, who were antiretroviral therapy-naïve with CD4+ ≥ 500 cells/mm3 , viral load ≤10 000 copies/mL, and asymptomatic over 10 years after HIV seroconversion. The primary outcome variable was HIV elite control (undetectable viral load in at least 90% of the measurements for at least 1 year). Seven IRF5-TNPO3 polymorphisms were genotyped using Agena Bioscience's MassARRAY platform. We found a significant association between specific IRF5-TNPO3 genotypes and HIV elite control: rs2004640 TT (aOR = 2.05; p = 0.041), rs10954213 AA (aOR = 1.95; p = 0.035), rs2280714 TT (aOR = 2.02; p = 0.031), and rs10279821 CC (aOR = 2.12; p = 0.017). We also found a significant association between IRF5-TNPO3 haplotype TATC composed of the favorable significant polymorphisms (rs2004640, rs10954213, rs2280714, and rs10279821) and the HIV elite control (aOR = 1.59; p = 0.048). IRF5-TNPO3 rs2004640, rs10954213, rs2280714, and rs10279821 polymorphisms were related to HIV elite control in LTNPs. Our data provide new knowledge about the impact of IRF5-TNPO3 polymorphisms on HIV pathogenesis to understand the phenomenon of natural HIV control.

Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

The pro-inflammatory phenotype of microglia usually induces neuroinflammatory reactions in neuropathic pain. Glycometabolism shift to glycolysis can promote the pro-inflammatory phenotype transition of microglia. The omics data analysis suggest a critical role for Lyn dysregulation in neuropathic pain. The present study aimed at exploring the mechanism of Lyn-mediated glycolysis enhancement of microglia in neuropathic pain. Neuropathic pain model was established by chronic constriction injury (CCI), then pain thresholds and Lyn expression were measured. Lyn inhibitor Bafetinib and siRNA-lyn knockdown were administrated intrathecally to evaluate the effects of Lyn on pain thresholds, glycolysis and interferon regulatory factor 5 (IRF5) nuclear translocation of microglia in vivo and in vitro. ChIP was carried out to observe the binding of transcription factors SP1, PU.1 to glycolytic gene promoters by IRF5 knockdown. Finally, the relationship between glycolysis and pro-inflammatory phenotype transition of microglia was evaluated. CCI led to the upregulation of Lyn expression and glycolysis enhancement in microglia of spinal dorsal horn. Bafetinib or siRNA-lyn knockdown intrathecally alleviated pain hyperalgesia, suppressed glycolysis enhancement and inhibited nuclear translocation of IRF5 in CCI mice. Also, IRF5 promoted the binding of transcription factors SP1, PU.1 to glycolytic gene promoters, and then the enhanced glycolysis facilitated the proliferation and pro-inflammatory phenotype transition of microglia and contributed to neuropathic pain. Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

Sex differences in the percentage of IRF5 positive B cells are associated with higher production of TNF-α in women in response to TLR9 in humans.

BACKGROUND: The clinical course and outcome of many diseases differ between women and men, with women experiencing a higher prevalence and more severe pathogenesis of autoimmune diseases. The precise mechanisms underlying these sex differences still remain to be fully understood. IRF5 is a master transcription factor that regulates TLR/MyD88-mediated responses to pathogen-associated molecular patterns (PAMPS) in DCs and B cells. B cells are central effector cells involved in autoimmune diseases via the production of antibodies and pro-inflammatory cytokines as well as mediating T cell help. Dysregulation of IRF5 expression has been reported in autoimmune diseases, including systemic lupus erythematosus, primary Sjögren syndrome, and rheumatoid arthritis. METHODS: In the current study, we analyzed whether the percentage of IRF5 positive B cells differs between women and men and assessed the resulting consequences for the production of inflammatory cytokines after TLR7- or TLR9 stimulation. RESULTS: The percentage of IRF5 positive B cells was significantly higher in B cells of women compared to men in both unstimulated and TLR7- or TLR9-stimulated B cells. B cells of women produced higher levels of TNF-α in response to TLR9 stimulation. CONCLUSIONS: Taken together, our data contribute to the understanding of sex differences in immune responses and may identify IRF5 as a potential therapeutic target to reduce harmful B cell-mediated immune responses in women.

Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) and concurrent depression are predisposed to severer disease activity and a worse prognosis. Macrophage polarization toward the M1 phenotype may contribute to the exacerbation of IBD with comorbid depression. Moreover, interferon regulatory factor 5 (IRF5) is involved in the pathogenesis of IBD. The aim of this study was to explore the role of IRF5 in macrophage polarization in the impact of depression upon colitis. METHODS: Depressive-like behavior was induced by repeated forced swim stress. Colon length, disease activity index (DAI), colon morphology, histology, ultrastructure of epithelial barrier, lamina propria macrophage polarization, and expression of IRF5 were compared between DSS colitis rats with and without depressive-like behavior. IRF5 shRNA was constructed to affect the rat peritoneal macrophages polarization in vitro. After IRF5 shRNA lentivirus was introduced into colon by enema, the colitis severity, lamina propria macrophage polarization, and TNF-α, IL-1ß, and IL-10 of colon tissues were measured. RESULTS: The study found severer colonic inflammation in depressed versus non-depressed DSS-colitis rats. Depressed DSS-colitis rats exhibited smaller subepithelial macrophages size and reduced intracellular granule diversity compared with nondepressed DSS-colitis rats. Increased polarization toward the M1 phenotype, elevated expression of IRF5, and co-expression of IRF5 with CD86 were found in depressed versus nondepressed DSS-colitis rats. Lentivirus-mediated shRNA interference with IRF5 expression switched rat peritoneal macrophage polarization from the M1 to the M2 phenotype, downregulated TNF-α, IL-1ß expression to a greater extent in depressed versus nondepressed colitis rats. CONCLUSIONS: IRF5-mediated macrophage polarization may likely underlie the deterioration of DSS-induced colitis caused by depression.

Frequency of IRF5+ dendritic cells is associated with the TLR7-induced inflammatory cytokine response in SARS-CoV-2 infection.

The SARS-CoV-2 infection leads to enhanced inflammation driven by innate immune responses. Upon TLR7 stimulation, dendritic cells (DC) mediate the production of inflammatory cytokines, and in particular of type I interferons (IFN). Especially in DCs, IRF5 is a key transcription factor that regulates pathogen-induced immune responses via activation of the MyD88-dependent TLR signaling pathway. In the current study, the frequencies of IRF5+ DCs and the association with innate cytokine responses in SARS-CoV-2 infected individuals with different disease courses were investigated. In addition to a decreased number of mDC and pDC subsets, we could show reduced relative IRF5+ frequencies in mDCs of SARS-CoV-2 infected individuals compared with healthy donors. Functionally, mDCs of COVID-19 patients produced lower levels of IL-6 in response to in vitro TLR7 stimulation. IRF5+ mDCs more frequently produced IL-6 and TNF-α compared to their IRF5- counterparts upon TLR7 ligation. The correlation of IRF5+ mDCs with the frequencies of IL-6 and TNF-α producing mDCs were indicators for a role of IRF5 in the regulation of cytokine responses in mDCs. In conclusion, our data provide further insights into the underlying mechanisms of TLR7-dependent immune dysfunction and identify IRF5 as a potential immunomodulatory target in SARS-CoV-2 infection.

The impact and interaction of TLR2 and IRF-5 gene polymorphisms on the susceptibility to neonatal sepsis / 中国医师杂志

Objective:To investigate the impact and interaction of Toll like receptor 2 (TLR2) and interferon regulatory factor 5 (IRF-5) gene polymorphisms on the susceptibility to neonatal sepsis.Methods:A total of 78 cases of neonatal septicemia patients admitted to Baoding Children′s Hospital from July 2018 to August 2021 were prospectively selected as the study group, and 78 cases of healthy newborns in the same period were selected as the control group. The TLR2 and IRF-5 gene polymorphisms and the levels of inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in different genotypes of infants were compared between the two groups. We evaluated the relationship between TLR2 and IRF-5 genotypes, inflammatory markers, and susceptibility to neonatal sepsis, and analyzed the interaction between their gene polymorphisms and susceptibility to neonatal sepsis.Results:There were significant differences in the distribution of TLR2 (rs3804099) and IRF-5 (rs2004640) loci genotype and Allele frequency between the two groups (all P<0.05); The serum CRP, TNF-α, and IL-6 levels in children with TLR2 (rs3804099) genotype TT genotype [(111.12±30.87)mg/L, (77.50±20.02)pg/ml, (40.27±11.31)pg/ml] were higher than those in children with CC/CT genotype [(72.46±24.51)mg/L, (54.18±17.65)pg/ml, (28.34±9.05)pg/ml], and the differences were statistically significant (all P<0.05). The serum CRP, TNF-α, and IL-6 levels [(113.90±28.94)mg/L, TNF-α (79.84±19.82)pg/ml, IL-6 (41.05±11.49)pg/ml] in children with the IRF-5 (rs2004640) TT genotype were higher than those in children with the GG/GT genotype [(70.88±22.16)mg/L, (52.27±16.73)pg/ml, (27.96±9.75)pg/ml], and the differences were statistically significant (all P<0.05). The TT genotypes at TLR2 (rs3804099) and IRF-5 (rs2004640) loci were positively correlated with serum CRP, TNF-α, and IL-6 levels (all P<0.05); The TT genotypes at TLR2 (rs3804099) and IRF-5 (rs2004640) loci were independent risk factors for susceptibility to neonatal sepsis (all P<0.05); The TT genotype at the TLR2 (rs3804099) locus and the TT genotype at the IRF-5 (rs2004640) locus exhibited a positive interaction in susceptibility to neonatal sepsis ( OR=7.467, γ=1.728). Conclusions:TLR2 (rs3804099) TT genotype and IRF-5 (rs2004640) TT genotype significantly increase the susceptibility to neonatal sepsis, and there is a positive interaction between the two.

microRNA-144/451 decreases dendritic cell bioactivity via targeting interferon-regulatory factor 5 to limit DSS-induced colitis.

The microRNAs miR-144/451 are highly conserved miRNA that is strongly induced during erythropoiesis. Despite the biological functions of miR-144/451 have been extensively studied in erythropoiesis and tumorigenesis, few studies have been conducted in immune responses. In this study, we showed that miR-144/451-/- DCs exhibit increased activation. Mechanistically, the miR-144 directly targets the 3`-UTR of IRF5 and represses the expression of IRF5 in DCs. Ectopic expression of miR-144/451 by lentiviruses downregulates the levels of IRF5 and suppresses DCs function. In addition, knockdown of IRF5 by shRNA significantly inhibits activities of the miR-144/451-/- DCs. Expression of miR144/451 was decreased in DCs from both patients with IBD and mice with DSS-colitis compared with controls. Human PBMC derived DCs were downregulated expression of miR144/451 after LPS stimulation. In the DSS-induced colitis mice model, we showed that ablation of the miR-144/451 gene causes severe colitis, and their DCs from both periphery and MLN expressed higher co-stimulatory molecules and pro-inflammatory cytokines than wild-type mice. In addition, DCs isolated from miR-144/451-/- mice transfusion exacerbates mice colitis. In the bone marrow transplanted chimeric mice model, we show that miR-144/451-/- bone marrow transplantation deteriorated DSS-induced colitis. At last, we treat the mice with miR-144/451 delivered by chitosan nanoparticles revealing protective effects in DSS-induced colitis mice. Thus, our results reveal a novel miR144/451-IRF5 pathway in DCs that protects experimental colitis. The manipulation of miR-144/451 expression and DCs activation in IBD patients may be a novel therapeutic approach for the treatment of inflammatory diseases.

Relationship of interferon regulator factor 5 and interferon-γ with missed abortion.

The aim of the present study was to reveal the association of missed abortion, a process integrated with the immune system, with interferon regulatory factor 5 (IRF5) and interferon-γ (IFN-γ), and to demonstrate the function of these molecules by examining their levels in decidual tissue. This prospective cohort study included 13 patients with no additional systemic disease, between 6 and 10 weeks of gestation with negative fetal heartbeat, and 11 patients between 6 and 10 weeks of gestation with positive heartbeat who presented for voluntary termination of pregnancy. In the fresh decidual tissue materials recovered after therapeutic curettage, IFN-γ and IRF5 protein levels were determined by ELISA method and IFN-γ and IRF5 gene expression levels by qPCR method. The mean IFN-γ (86.5 vs. 27.3 pg/mg protein; P<0.001) and IRF5 (2.0 vs. 1.5 ng/mg protein; P<0.001) levels were significantly higher in pregnant women who had missed abortion compared to the voluntary abortion group. The increases in the mean IFN-γ/GAPDH (3.5 vs. 1.5-fold increase; P<0.001) and IRF5/GAPDH (3.9 vs. 1.4-fold increase; P<0.001) gene expression levels were significantly higher in the tissues of pregnant women with missed abortion than in the voluntary abortion group. A threshold value of 45.2 pg/mg protein for IFN-γ had a sensitivity of 100% and specificity of 100% in determination of missed abortion. The findings of present study revealed, to the best of our knowledge for the first time in the literature, that IFN-γ and IRF5 may be associated with missed abortion, and that IFN-γ and IRF5 protein levels and gene expression levels were significantly increased in the case of missed abortion. According to our findings, IFN-γ and IRF5 play an important role in placental invasion and pregnancy and can be used as markers for endometrial implantation.

Interferon regulatory factor 5­induced upregulation of zinc­finger protein 217 promotes pancreatic carcinoma progression.

The aim of the present study was to investigate the molecular mechanisms of zinc­finger protein 217 (ZNF217) in pancreatic carcinoma (PC) progression. ZNF217­associated expression and survival data from patients with PC were retrieved from the Gene Expression Profiling Interactive Analysis server. The mRNA expression level of ZNF217 was detected by reverse transcription­quantitative PCR. Cell Counting Kit­8, colony formation, wound­healing and Transwell assays were conducted to assess cellular proliferation, migratory and invasive abilities. Proliferation was also examined by immunofluorescence detection of Ki67 expression, and chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to detect the interaction between ZNF217 and interferon regulatory factor 5 (IRF5). ZNF217 was found to be significantly upregulated in tumor tissues and cancer cell lines, which was associated with a poor survival rate in patients with PC. ZNF217 silencing markedly suppressed cellular proliferation and migratory and invasive abilities, as well as decreased the expression of Ki67. IRF5 was also upregulated in PC tumor tissues and was shown to positively regulate the activity of the ZNF217 promoter and its mRNA expression levels. Furthermore, ChIP assays demonstrated that IRF5 bound to the promoter region of ZNF217 in vitro. In conclusion, ZNF217 silencing exerted notable inhibitory effects on the progression of PC. Thus, ZNF217 may serve as a potential target for developing novel therapeutic strategies for PC.

The risk factor for instability metabolic health and severity.

Coronavirus disease -19 (COVID-19) pandemic has extended from late 2019 and continues to this day. The degree of the disease is related to some factors, including age and comorbidities. Obesity is now more widely considered as a main factor of infection, mainly because it has been shown that individuals who are obese have a more severe course of infection with COVID-19. This review study summarized the relationship between the risk of obesity and COVID-19 and detected a difference in reporting from the period of the first pandemic in China to more recent studies. Obesity is a risk factor for developing signs and symptoms of patients with COVID-19 and this review will benefit clinicians by recognizing the role of obesity when giving COVID-19 diagnosis, follow-up, and treatment programs.

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe-/- mice.

OBJECTIVE: Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis. METHODS: Female Apoe-/-LysmCre/+Irf5fl/fl and Apoe-/-Irf5fl/fl mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques. RESULTS: Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo. While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5-deficient Apoe-/- mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfß expression. Irf5-deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5-deficient macrophages proliferated less in the plaque. CONCLUSION: Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.

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.

MicroRNA-22-3p alleviates spinal cord ischemia/reperfusion injury by modulating M2 macrophage polarization via IRF5.

Cell death after spinal cord ischemia/reperfusion (I/R) can occur through necrosis, apoptosis, and autophagy, resulting in changes to the immune environment. However, the molecular mechanism of this immune regulation is not clear. Accumulating evidence indicates that microRNAs (miRs) play a crucial role in the pathogenesis of spinal cord I/R injury. Here, we hypothesized miR-22-3p may be involved in spinal cord I/R injury by interacting with interferon regulatory factor (IRF) 5. Rat models of spinal cord I/R injury were established by 12-min occlusion of the aortic arch followed by 48-hr reperfusion, with L4-6 segments of spinal cord tissues collected. MiR-22-3p agomir, a lentivirus-delivered siRNA specific for IRF5, or a lentivirus expressing wild-type IRF5 was injected intrathecally to rats with I/R injury to evaluate the effects of miR-22-3p and IRF5 on hindlimb motor function. Macrophages isolated from rats were treated with miR-22-3p mimic or siRNA specific for IRF5 to evaluate their effects on macrophage polarization. The levels of IL-1ß and TNF-α in spinal cord tissues were detected by ELISA. miR-22-3p was down-regulated, whereas IRF5 was up-regulated in rat spinal cord tissues following I/R. IRF5 was a target gene of miR-22-3p and could be negatively regulated by miR-22-3p. Silencing IRF5 or over-expressing miR-22-3p relieved inflammation, elevated Tarlov score, and reduced the degree of severity of spinal cord I/R injury. Increased miR-22-3p facilitated M2 polarization of macrophages and inhibited inflammation in tissues by inhibiting IRF5, thereby attenuating spinal cord I/R injury. Taken together, these results demonstrate that increased miR-22-3p can inhibit the progression of spinal cord I/R injury by repressing IRF5 in macrophages, highlighting the discovery of a promising new target for spinal cord I/R injury treatment.

IRF5 Signaling in Phagocytes Is Detrimental to Neonatal Hypoxic Ischemic Encephalopathy.

Immune responses to neonatal hypoxic ischemic encephalopathy (HIE) exacerbate brain injury. Phagocytes, including microglia, play a central role in the immune response, but how the activation of phagocytes is regulated remains elusive. Previously, we have reported that interferon regulatory factor 5 (IRF5) signaling is closely correlated with a pro-inflammatory microglial phenotype in adult mice after stroke. The present study investigated IRF5's regulatory role in post-HIE inflammation. Male IRF5 conditional knockout (CKO) and IRF5fl/fl postnatal day 10 (P10) pups were subjected to the Rice-Vannucci model (RVM) to induce HIE. Outcomes including morphological and neurobehavioral changes were evaluated at day 7 after HIE. Microglia/macrophage phenotypes and inflammatory responses were evaluated by flow cytometry (FC), RT-PCR, and multiplex cytokine assays. Lenti-IRF5 virus was administered in microglia-neuron co-cultures to evaluate the effects of microglial IRF5 upregulation in ischemic neurons exposed to oxygen-glucose deprivation (OGD). Deletion of phagocytic IRF5 resulted in significantly decreased IRF5 expression, attenuated pro-inflammatory and enhanced anti-inflammatory responses to HIE, and improved outcomes compared with IRF5fl/fl control pups. In vitro lentivirus transfection experiments revealed that overexpression of IRF5 in microglia amplified pro-inflammatory signals and exacerbated OGD-induced neuronal apoptosis and neurite fragmentation. IRF5 signaling mediates microglial pro-inflammatory activation and also affects anti-inflammatory responses. Phagocytic IRF5 signaling is detrimental in HIE and is a potential therapeutic target for post-ischemic inflammation.

SB203580 protects against inflammatory response and lung injury in a mouse model of lipopolysaccharide­induced acute lung injury.

Acute lung injury (ALI) is characterized by acute hypoxic respiratory failure, pulmonary edema and inflammatory infiltration. ALI has a high mortality rate (~30%) in the clinical setting; therefore, focusing on the treatment of lung edema and inflammatory responses in ALI is of significance. The present study investigated the effect of the p38 mitogen­activated protein kinase (p38MAPK) inhibitor, SB203580, on lung edema and inflammatory responses in ALI in vivo. A mouse model of ALI was established to assess the effect of SB203580 on edema, proinflammatory cytokine production, and the expression of interferon regulatory factor 5 (IRF5) and inducible nitric oxide synthase (iNOS) in lung tissues using immunoblotting, immunohistochemistry, immunofluorescence, hematoxylin and eosin staining, and ELISA. SB203580 inhibited LPS­induced lung injury and proinflammatory cytokine expression, including tumor necrosis factor­α and interleukin­1ß. SB203580 also downregulated LPS­induced IRF5 and iNOS expression, which are widely used as markers of proinflammatory macrophages. Collectively, the present study demonstrated that SB203580 protected against inflammatory responses and lung injury by inhibiting lung edema and downregulating proinflammatory mediators in LPS­induced lung injury.

Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice.

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset.

Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04-2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17-2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56-2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61-1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.