Role Of Macrophage Migration Inhibitory Factor Research Articles

MIF as a potential diagnostic and prognostic biomarker for triple-negative breast cancer that correlates with the polarization of M2 macrophages.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a crucial role in antitumor immunity. However, the role of MIF in influencing the tumor microenvironment (TME) and prognosis of triple-negative breast cancer (TNBC) remains to be elucidated. Using R, we analyzed single-cell RNA sequencing (scRNA-seq) data of 41 567 cells from 10 TNBC tumor samples and spatial transcriptomic data from two patients. Relationships between MIF expression and immune cell infiltration, clinicopathological stage, and survival prognosis were determined using samples from The Cancer Genome Atlas (TCGA) and validated in a clinical cohort using immunohistochemistry. Analysis of scRNA-seq data revealed that MIF secreted by epithelial cells in TNBC patients could regulate the polarization of macrophages into the M2 phenotype, which plays a key role in modulating the TME. Spatial transcriptomic data also showed that epithelial cells (tumor cells) and MIF were proximally located. Analysis of TCGA samples confirmed that tumor tissues of patients with high MIF expression were enriched with M2 macrophages and showed a higher T stage. High MIF expression was significantly associated with poor patient prognosis. Immunohistochemical staining showed high MIF expression was associated with younger patients and worse clinicopathological staging. MIF secreted by epithelial cells may represent a potential biomarker for the diagnosis and prognosis of TNBC and may promote TNBC invasion by remodeling the tumor immune microenvironment.

The human MIF polymorphism CATT7 enhances pro-inflammatory macrophage polarization in a clinically relevant model of allergic airway inflammation.

High level expression of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow-derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF-dependent, as administration of a small molecule MIF inhibitor, SCD-19, blocked the induction of this pro-inflammatory M1-like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro-inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM-induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8).

Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that "brings" cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 μM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.

The role of MIF in periodontitis: A potential pathogenic driver, biomarker, and therapeutic target.

Periodontitis is an inflammatory disease that involves an imbalance in the oral microbiota, activation of inflammatory and immune responses, and alveolar bone destruction. Macrophage migration inhibitory factor (MIF) is a versatile cytokine involved in several pathological reactions, including inflammatory processes and bone destruction, both of which are characteristics of periodontitis. While the roles of MIF in cancer and other immune diseases have been extensively characterized, its role in periodontitis remains inconclusive. In this review, we describe a comprehensive analysis of the potential roles of MIF in periodontitis from the perspective of immune response and bone regulation at the cellular and molecular levels. Moreover, we discuss its potential reliability as a novel diagnostic and therapeutic target for periodontitis. This review can aid dental researchers and clinicians in understanding the current state of MIF-related pathogenesis, diagnosis, and treatment of periodontitis.

Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury

Macrophage migration inhibitory factor (MIF) is a multifaced protein that plays important roles in multiple inflammatory conditions. However, the role of MIF in endothelial cell (EC) death under inflammatory condition remains largely unknown. Here we show that MIF actively promotes receptor-interacting protein kinase 1 (RIPK1)-mediated cell death under oxygen-glucose deprivation condition. MIF expression is induced by surgical trauma in peripheral myeloid cells both in perioperative humans and mice. We demonstrate that MIF-loaded myeloid cells induced by peripheral surgery adhere to the brain ECs after distal middle cerebral artery occlusion (dMCAO) and exacerbate the blood-brain barrier (BBB) disruption. Genetic depletion of myeloid-derived MIF in perioperative ischemic stroke (PIS) mice with MCAO following a surgical insult leads to significant reduction in ECs apoptosis and necroptosis and the associated BBB disruption. The adoptive transfer of peripheral blood mononuclear cells (PBMC) from surgical MIFΔLyz2 mice to wild-type (WT) MCAO mice also shows reduced ECs apoptosis and necroptosis compared to the transfer of PBMC from surgical MIFf l/f l mice to MCAO recipients. The genetic inhibition of RIPK1 also attenuates BBB disruption and ECs death compared to that of WT mice in PIS. The administration of MIF inhibitor (ISO-1) and RIPK1 inhibitor (Nec-1s) can both reduce the brain EC death and neurological deficits following PIS. We conclude that myeloid-derived MIF promotes ECs apoptosis and necroptosis through RIPK1kinase-dependent pathway. The above findings may provide insights into the mechanism as how peripheral inflammation promotes the pathology in central nervous system.

Macrophage migration inhibitory factor MtMIF3 prevents the premature aging of Medicago truncatula nodules.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in immune response in animals. However, the role of MIFs in plants such as Medicago truncatula, particularly in symbiotic nitrogen fixation, remains unclear. An investigation of M. truncatula-Sinorhizobium meliloti symbiosis revealed that MtMIF3 was mainly expressed in the nitrogen-fixing zone of the nodules. Silencing MtMIF3 using RNA interference (Ri) technology resulted in increased nodule numbers but higher levels of bacteroid degradation in the infected cells of the nitrogen-fixing zone, suggesting that premature aging was induced in MtMIF3-Ri nodules. In agreement with this conclusion, the activities of nitrogenase, superoxide dismutase and catalase were lower than those in controls, but cysteine proteinase activity was increased in nodulated roots at 28 days postinoculation. In contrast, the overexpression of MtMIF3 inhibited nodule senescence. MtMIF3 is localized in the plasma membrane, nucleus, and cytoplasm, where it interacts with methionine sulfoxide reductase B (MsrB), which is also localized in the chloroplasts of tobacco leaf cells. Taken together, these results suggest that MtMIF3 prevents premature nodule aging and protects against oxidation by interacting with MtMsrB.

Plasma Macrophage Migration Inhibitory Factor Concentration at Each Spectrum of Tuberculosis.

Macrophage migration inhibitory factor (MIF) is an inflammatory mediator in several diseases, including tuberculosis (TB). However, the role of MIF in each stage of TB remains to be further elucidated. Thus, this study aimed to analyze the differences in plasma MIF protein levels in patients with active pulmonary TB, positive and negative interferon-gamma release assay (IGRA) household contacts (HHCs), and healthy controls (HCs). Plasma MIF concentration was significantly higher in patients with active-new pulmonary tuberculosis (ATB) and HHCs compared with HCs (mean ± standard deviation: 17.32 ± 16.85, 16.29 ± 14.21, and 7.29 ± 5.39 ng/mL, respectively; P = 0.002). The plasma MIF concentration was not statistically different when compared between patients with ATB, IGRA-positive HHCs (17.44 ± 16.6 ng/mL), and IGRA-negative HHCs (14.34 ± 8.7 ng/mL) (P = 0.897). In conclusion, ATB patients, IGRA-positive HHCs, and IGRA-negative HHCs have a higher MIF concentration than HCs. This shows the involvement of MIF in each stage of TB, starting from TB exposure and infection, but not symptomatic, to the active stage.

Deep Insight into the Role of MIF in Spondyloarthritis.

Pathological roles of macrophage migration inhibitory factor (MIF) have recently been demonstrated in spondyloarthritis (SpA) preclinical models, identifying MIF as a new treatment target for SpA. However, the specific contribution of MIF and therapeutic potential of MIF-targeted therapies to various tissue types affected by SpA are not well delineated. MIF and its cognate receptor CD74 are extensively involved in the pathogenesis of SpA including inflammation in the spine, joint, eyes, skin, and gut. The majority of the current evidence has consistently shown that MIF drives the inflammation in these distinct anatomical sites. In preclinical models, genetic deletion or blockade of MIF reduces the severity of inflammation. Although MIF is generally an upstream cytokine which regulates downstream effector cytokines, MIF also intensifies type 3 immunity by promoting helper T 17 (Th17) plasticity. MIF- or CD74-targeted therapies have also reported to be well tolerated in clinical trials for other diseases. Recent findings suggest that MIF-CD74 axis is a new therapeutic target for SpA to improve various clinical features. Clinical trials for MIF- or CD74-targeted therapies for SpA patients are warranted.

MIF/CXCR4 signaling axis contributes to survival, invasion, and drug resistance of metastatic neuroblastoma cells in the bone marrow microenvironment

BackgroundThe bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying the aggressive behavior of NB cells in the BM niche are still greatly unknown. In the present study, we explored biological mechanisms that play a critical role in NB cell survival and progression in the BM and investigated potential therapeutic targets.MethodsPatient-derived bone marrow (BM) primary cultures were generated using fresh BM aspirates obtained from NB patients. NB cell lines were cultured in the presence of BM conditioned media containing cell-secreted factors, and under low oxygen levels (1% O2) to mimic specific features of the BM microenvironment of high-risk NB patients. The BM niche was explored using cytokine profiling assays, cell migration-invasion and viability assays, flow cytometry and analysis of RNA-sequencing data. Selective pharmacological inhibition of factors identified as potential mediators of NB progression within the BM niche was performed in vitro and in vivo.ResultsWe identified macrophage migration inhibitory factor (MIF) as a key inflammatory cytokine involved in BM infiltration. Cytokine profiling and RNA-sequencing data analysis revealed NB cells as the main source of MIF in the BM, suggesting a potential role of MIF in tumor invasion. Exposure of NB cells to BM-conditions increased NB cell-surface expression of the MIF receptor CXCR4, which was associated with increased cell viability, enhanced migration-invasion, and activation of PI3K/AKT and MAPK/ERK signaling pathways. Moreover, subcutaneous co-injection of NB and BM cells enhanced tumor engraftment in mice. MIF inhibition with 4-IPP impaired in vitro NB aggressiveness, and improved drug response while delayed NB growth, improving survival of the NB xenograft model.ConclusionsOur findings suggest that BM infiltration by NB cells may be mediated, in part, by MIF-CXCR4 signaling. We demonstrate the antitumor efficacy of MIF targeting in vitro and in vivo that could represent a novel therapeutic target for patients with disseminated high-risk NB.

Evaluation of Macrophage Migration Inhibitory Factor (MIF) Level as a Biomarker for Rheumatoid Arthritis among Iraqi Patients

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease. MIF protein is one of proinflammatory cytokines has been implicated in various inflammatory and immune-mediated diseases. Therefore, the goal of the study was to assess the role of MIF in the pathogenesis of RA in Iraqi patient. One hundred and eighty (180) participants were involved; ninety patients with RA and ninety healthy controls. All participants were assessed by the following diagnostic lab analyses: RF, Anti-CCP, ESR, CRP and CBC to confirm RA disease. MIF level were evaluated in participants' sera by using ELISA assay. The age mean of RA patients was (52.03 ± 13.01); the patients more than 50 years age represent 57.80%. Significant difference was recorded in male and female frequencies among patients and controls (p=0.023). The mean of RA patients' body weight was (83.68 ± 14.15). According to disease duration, more than 10 years of disease duration was the most frequent (44.4%). Disease activity score recorded that (55.6%) of patients represent a moderate RA activity. Median levels of RF, CRP, Anti-CCP Abs and ESR recorded a significant increase in RA patients' sera; RBCs and HGB recorded lower values in patients of RA compared to control group; WBCs, lymphocyte and PLT count recorded no significant differences between the study groups (p-value>0.05 for all), while significant high value of neutrophils was recorded in RA patients than in healthy control (p<0.001). The mean of MIF serum level showed significant increase in RA patients compared to controls (22.51 vs. 4.33 ng/ml; p< 0.001); receiver operator characteristics curve (ROC) of MIF indicated that MIF was a predictor of RA. Patients at the age group (20 – 29 years) showed a significant increased mean of MIF level compared to other age groups of patients; no significant differences between MIF level and disease activity score in RA patients. In conclusion, MIF is an important biomarker for RA that may have a role in the pathogenesis of this disease.

The biomarker macrophage migration inhibitory factor as a predictor of no-reflow phenomenon and other adverse events in patients with ST-segment elevation myocardial infarction

Abstract Major adverse cardiovascular events (MACE) in patients with ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) may be caused by the “no-reflow” phenomenon. Biomarkers for the “no-reflow” phenomenon prediction is being actively studied. Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is one of the promising biomarkers. Purpose To estimate the role of MIF in the prediction of early reperfusion myocardial injury and MACE in patients with STEMI. Methods The study involved 341 STEMI patients (78.6% male and 21.4% female) with an average age of 59.08±9.65 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF and soluble suppression of tumorigenicity-2 (sST2) determined twice during the first 12 hours of STEMI, before the PCI and 24 hours after the procedure. Coronary blood flow evaluated using TIMI flow grade and myocardial blush grade (MBG). All patients had epicardial blood flow TIMI 3. The criteria for “no-reflow” diagnosis were myocardial perfusion at MBG 0 or MBG 1 level with complete recovery of epicardial blood flow or ST-segment resolution (rST) of less than 70% from baseline within 2 hours after PCI. All patients were divided into two groups according to MBG and rST after PCI more and less than 70%: 147 patients in the first group with MBG stage 0–1, 182 patients with MBG stage 2–3. Results The level of MIF biomarker determined before PCI was significantly higher in the group of patients with MBG 0–1 in comparison to MBG 2–3. (4386,750±676 pg/ml vs 2935±350 pg/ml; p=0,05). Also, the level of sST2, left ventricular mass index and blood glucose were significantly higher in the group of MBG 0–1 (p=0.03, p=0.006 and p=0.0085, respectively). The difference in left ventricle posterior wall thickness and early to late diastolic transmitral flow velocity (p=0.045) was found between two groups. In the group of MBG 0–1 and rST<70% these parameters were significantly lower (p=0,04 and p=0,05, respectively). Using the multivariate regression analysis, the dependency of the biomarker MIF on the parameters of the reperfusion myocardial injuries were obtained. MIF measured before revascularization was an independent predictor of MBG 0–1 and rST less than 70% (coefficients Beta 0,00057; odd ratio 1,0; 95%confidential interval (CI) 1,0–1,001; p=0,038). The Kaplan-Meier survival analysis showed that long-term adverse outcomes rate after STEMI was significantly higher in patient with the level of MIF determined during the first 12 hours after the event more than 2988 pg/ml (Log-rank = −4,891, p=0.014). Conclusions Biomarkers MIF has a capacity as predictive tool for MACE and “no-reflow” phenomenon in STEMI patients. Funding Acknowledgement Type of funding sources: None.

Circulating MIF Associated With Disease Severity and Clinical Response of Sublingual Immunotherapy in House Dust Mite-Induced Allergic Rhinitis.

Background: Macrophage migration inhibitory factor (MIF) is described as a pro-inflammatory cytokine involved in many inflammatory and allergic disorders, but the role of MIF in allergic rhinitis (AR) remains poorly clarified. The aim of this study was to investigate the association between circulating MIF levels and house dust mite (HDM)-induced AR, and evaluate MIF as a potential biomarker in reflecting disease severity and predicting the clinical response of sublingual immunotherapy (SLIT) in HDM-induced AR patients. Methods: In this study, we enrolled 160 persistent HDM-induced AR patients (AR group), including 48 mild AR patients (MAR group) and 112 moderate–severe AR patients (MSAR group), and 77 healthy controls (HC group). Circulating levels of MIF were measured by ELISA, and the relationship between MIF concentrations and disease severity was assessed. In the MSAR group, 106 patients were assigned to receive SLIT for 3 years. At the end of the study, patients were categorized into good response group and poor response group, and associations between clinical variables or biomarkers and clinical response were analyzed by the multivariate regression analysis. Results: The concentrations of serum MIF were significantly higher in AR patients than in HCs, especially in those with MSAR. Moreover, circulating MIF levels were positively correlated with TNSS, VAS, serum HDM–specific IgE, total IgE, blood eosinophil count, and blood eosinophil percentage (all p < 0.05). Eighty MSAR patients finally completed SLIT, 45 patients obtained good response, and 35 patients resulted in poor response. The serum levels of MIF were significantly lower in the good-response group than in the poor-response group (p < 0.001). The receiver operating characteristic analysis for MIF showed good accuracy for predicting clinical response of SLIT (area under the curve = 0.877, p < 0.001). The multivariate regression analysis demonstrated that serum MIF was an independent factor for SLIT responsiveness. Conclusion: Serum MIF appeared to be an important biological indicator in reflecting disease severity and an independent predictor for clinical responsiveness of SLIT in HDM-induced AR patients.

Role of MIF in coordinated expression of hepatic chemokines in patients with alcohol-associated hepatitis.

The chemokine system of ligands and receptors is implicated in the progression of alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. This study involved coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in 2 distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific KO were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. Selected C-X-C chemokine members of the IL-8 chemokine family and C-C chemokine CCL20 were highly associated with AH compared with HC but not in patients with liver diseases of other etiologies (nonalcoholic fatty liver disease [NAFLD] and hepatitis C virus [HCV]). Our previous studies implicate macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of WT mice; this was prevented in hepatocyte-specific Mif–KO (MifΔHep) mice. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and that hepatocyte-derived MIF might drive this inflammatory response.

Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src/PI3K/myosin II pathway

Constitutively expressed by innate immune cells, the cytokine macrophage migration inhibitory factor (MIF) initiates host immune responses and drives pathogenic responses in infectious, inflammatory, and autoimmune diseases. Dendritic cells (DCs) express high levels of MIF, but the role of MIF in DC function remains poorly characterized. As migration is critical for DC immune surveillance, we investigated whether MIF promoted the migration of DCs. In classical transwell experiments, MIF-/- bone marrow-derived DCs (BMDCs) or MIF+/+ BMDCs treated with ISO-1, an inhibitor of MIF, showed markedly reduced spontaneous migration and chemotaxis. CD74-/- BMDCs that are deficient in the ligand-binding component of the cognate MIF receptor exhibited a migration defect similar to that of MIF-/- BMDCs. Adoptive transfer experiments of LPS-matured MIF+/+ and MIF-/- and of CD74+/+ and CD74-/- BMDCs injected into the hind footpads of homologous or heterologous mice showed that the autocrine and paracrine MIF activity acting via CD74 contributed to the recruitment of DCs to the draining lymph nodes. Mechanistically, MIF activated the Src/PI3K signaling pathway and myosin II complexes, which were required for the migration of BMDCs. Altogether, these data show that the cytokine MIF exerts chemokine-like activity for DC motility and trafficking.

Macrophage migration inhibitory factor as a therapeutic target after traumatic spinal cord injury: a systematic review.

Macrophages play an important role in mediating damage after Spinal cord injury (SCI) by secreting macrophage migration inhibitory factor (MMIF) as a secondary injury mediator. We aimed to systematically review the role of MMIF as a therapeutic target after traumatic SCI. Our systematic review has been performed according to the PRISMA 2009 Checklist. A systematic search in the scientific databases was carried out for studies published before 20 February 2019 from major databases. Two researchers independently screened titles. The risk of bias of eligible articles was assessed, and data were extracted. Finally, we systematically analyzed and interpreted related data. 785 papers were selected for the title and abstract screening. 12 papers were included for data extraction. Eight animal studies were of high quality and the remaining two were of medium quality. One of the two human studies was of poor quality and the other was of fair quality. MMIF as a pro-inflammatory mediator can cause increased susceptibility to glutamate-related neurotoxicity, increased nitrite production, increased ERK activation, and increased COX2/PGE2 signaling pathway activation and subsequent stimulation of CCL5-related chemotaxis. Two human studies and six animal studies demonstrated that MMIF level increases after SCI. MMIF inhibition might be a potential therapeutic target in SCI by multiple different mechanisms (6/12 studies). Most animal studies demonstrate significant neurologic improvement after administration of MMIF inhibitors, but these inhibitors have not been studied in humans yet. Further clinical trials are need to further understand MMIF inhibitor utility in acute or chronic SCI. Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive impairment after bacterial meningitis

BackgroundPatients with pneumococcal meningitis are at risk for death and neurological sequelae including cognitive impairment. Functional genetic polymorphisms of macrophage migration inhibitory factor (MIF) alleles have shown to predict mortality of pneumococcal meningitis.MethodsWe investigated whether MIF concentrations during the acute phase of disease were predictive for death in a nationwide prospective cohort study. Subsequently, we studied whether individual ex vivo MIF response years after meningitis was associated with the development of cognitive impairment.ResultsWe found that in the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were predictive for mortality (p = 0.009). Cognitive impairment, examined 1–5 years after meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared to 1 of 63 (2%) in controls, and was consistently associated with individual variability in MIF production by peripheral blood mononuclear cells after ex vivo stimulation with various infectious stimuli.ConclusionsOur study confirms the role of MIF in poor disease outcome of pneumococcal meningitis. Inter-individual differences in MIF production were associated with long-term cognitive impairment years after pneumococcal meningitis. The present study provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

The Role of Macrophage Migration Inhibitory Factor (MIF) in Asthmatic Airway Remodeling.

PurposeRecent studies have demonstrated that macrophage migration inhibitory factor (MIF) is of importance in asthmatic inflammation. The role of MIF in modulating airway remodeling has not yet been thoroughly elucidated to date. In the present study, we hypothesized that MIF promoted airway remodeling by intensifying airway smooth muscle cell (ASMC) autophagy and explored the specific mechanisms.MethodsMIF knockdown in the lung tissues of C57BL/6 mice was conducted by instilling intratracheally adeno-associated virus (AAV) vectors (MIF-mutant AAV9) into mouse lung tissues. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/−) was used to detect the role of autophagy in ovalbumin (OVA)-asthmatic murine models. Moreover, to block the expression of MIF and CD74 in vitro models, inhibitors, antibodies and lentivirus transfection techniques were employed.ResultsFirst, MIF knockdown in the lung tissues of mice showed markedly reduced airway remodeling in OVA murine mice models. Secondly, ASMC autophagy was increased in the OVA-challenged models. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/−) that were primed and challenged with OVA showed lower airway remodeling than genetically wild-type asthmatic mice. Thirdly, MIF can induce ASMC autophagy in vitro. Moreover, the cellular source of MIF which promoted ASMC autophagy was macrophages. Finally, MIF promoted ASMC autophagy in a CD74-dependent manner.ConclusionsMIF can increase asthmatic airway remodeling by enhancing ASMC autophagy. Macrophage-derived MIF can promote ASMC autophagy by targeting CD74.

Increasing of Macrophage Migration Inhibitory Factor Expression in Human Patients Infected with Virulent Brucella in Iraq

Brucellosis is a zoonotic disease caused by Brucella infections and humans usually contract this disease from close contact with infected animals or their products, usually via the ingestion of cheese or crude milk. Macrophage migration inhibitory factor (MIF) and Pro- and anti-inflammatory cytokines play an important role in susceptibility/resistance and the immunopathogenesis of Brucella infection. These cytokines are crucial factors in the initiation and progression of protective immunity against Brucella infection but the role of MIF has not been well studied in the human response to intracellular microbes. This study was designed to investigate the effect of MIF expression on Brucella susceptibility. A total of 85 positive rose Bengal tests and 24 samples from healthy individuals were collected for this study and subjected to polymerase chain reaction assays (PCR) of the bcsp31 diagnostic gene. MIF concentrations were evaluated using Enzyme-Linked immunosorbent assay (ELISA) and the results showed that 46 (54%) of the rose Bengal test samples were positive and 39 (46%) were negative for bcsp31 (p ≤ 0.05) and used as the gold standard for all of the comparisons in this study. The ELISA results indicate that the mean concentration of MIF was significantly higher in patients with positive rose Bengal tests when compared to the control groups and that its concentration increases with increasing age in both the patient and control groups (p ≤ 0.05).

Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice

Overdose use of acetaminophen (APAP) often occurs a severe liver injury, and its liver injury is lethal in some cases. Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and has multifunctional roles. However, the role of MIF in APAP-induced liver injury has not been fully investigated. In this study, we investigated whether treatment with (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a MIF inhibitor, protected mice from acute APAP-induced liver injury. Acute liver injury was induced by injection of APAP (300 mg/kg body weight). Mice were treated with a single injection of ISO-1(15 mg/kg body weight) 1 h (h) before APAP administration. Histological, biochemical and molecular analyses were performed in liver of mice 12 h after APAP administration. ISO-1 remarkably improved the histological findings of APAP-induced liver injury in mice. The increases in serum levels of alanine aminotransferase (ALT), and macrophage inflammatory protein-2 (MIP-2) by APAP were inhibited by ISO-1. In addition, ISO-1 reduced the increased number of the myeloperoxidase-staining cells and that of TUNEL-positive staining cells in the liver of mice with APAP-induced liver injury. Up-regulation of hepatic receptor interacting protein kinase (RIPK)3 and heat shock protein70 by APAP was suppressed in the liver of mice given ISO-1. These results provide the additional evidence that inhibition of MIF activity may be clinically effective for treatment of acute APAP-induced liver injury.

A macrophage migration inhibitory factor as a predictor of reperfusion myocardial injury in patients with st-segment elevation myocardial infarction

Abstract Introduction Major adverse cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI) are still common despite the modern treatment approaches. It may be caused by the “no-reflow” phenomenon. One of the promising biomarkers for the coronary “no-reflow” phenomenon prediction is proinflammatory cytokine macrophage migration inhibitory factor (MIF). Purpose To estimate the role of MIF in the prediction of early reperfusion myocardial injury in patients with STEMI. Methods The study involved 341 STEMI patients (78.6% male and 21.4% female) with an average age of 59.08±9.65 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF determined twice during the first 12 hours of STEMI, before the percutaneous coronary intervention (PCI) and after the procedure. Coronary blood flow evaluated using TIMI flow grade and myocardial blush grade (MBG). All patients had epicardial blood flow TIMI 3. The criteria for “no-reflow” diagnosis were myocardial perfusion at MBG 0 or MBG 1 level with complete recovery of epicardial blood flow or ST-segment resolution (rST) of less than 70% from baseline within 2 hours after PCI. All patients were divided into two groups according to MBG and rST after PCI more and less than 70%: 147 patients in the first group with MBG stage 0–1, 182 patients with MBG stage 2–3 Results 64% of STEMI patients had elevated MIF levels above the highest value in healthy controls (2778±217 ng/ml; 225±6,7 ng/ml; p=0,0003). The level of MIF biomarker, determined before PCI was significantly higher in the group of patients with MBG 0–1 in comparison to MBG 2–3. (4708±471 ng/ml vs 2914±347ng/ml; p=0,004). Using the multivariate regression analysis, the dependencies of the biomarker MIF on the parameters of the reperfusion myocardial injuries were obtained. MIF measured before revascularization as well as the patient's gender, was an independent predictor of MBG 0–1 and rST less than 70% (coefficients Beta 0,1; odd ratio 1,1; 95%confidential interval (CI) 1,0–1,2; p=0,037 and coefficient Beta 2,9; odd ratio 17.7; 95% CI 0,96–32; p=0,05, respectively). Conclusions The study revealed that MIF predicts reperfusion myocardial injury in patients with STEMI. Future investigations of the MIF biological effects are the perspective direction in the field of modern cardiology. Funding Acknowledgement Type of funding source: None