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).

Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. METHODS: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose. RESULTS: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. CONCLUSIONS: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

Migration Inhibition Factor Secreted by Peripheral Blood Memory B Cells Binding to CD74-CD44 Receptor Complex Drives Macrophage Behavior in Alzheimer's Disease.

Dysregulation of the peripheral immune system is be involved in the neuroinflammation in Alzheimer disease (AD) and accelerate the disease progression. The contribution of immune cells, particularly B cells, to AD pathogenesis has gained attention in recent research. In this study, we investigated the role of Peripheral Blood Memory B cells (PBMBs) and their secreted Migration Inhibition Factor (MIF) in driving macrophage behavior in AD based on the scRNA-seq technique, immunofluorescence and flow cytometry. We discovered that MIF binds to the CD74-CD44 receptor complex on macrophages, influencing their behavior. The dysregulated macrophage response hampers the clearance of amyloid-beta (Aß) plaques, exacerbating AD pathology. Targeting the MIF-CD74-CD44 signal pathway may hold therapeutic potential in modulating macrophage activity and mitigating neuroinflammation in AD. This study provides a further understanding of peripheral immune cells dysregulated in AD.

Moxibustion of Zusanli (ST36) and Shenshu (BL23) alleviates the inflammation of rheumatoid arthritis in rats through regulating macrophage migration inhibitory factor/glucocorticoids signaling.

OBJECTIVE: To test the hypothesis that moxibustion may inhibit rheumatoid arthritis (RA) synovial inflammation by regulating the expression of macrophage migration inhibitory factor (MIF)/glucocorticoids (GCs). METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (n = 10 each): blank Control (CON) group, RA Model (RA) group, Moxibustion (MOX) group, MIF inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) group, and Moxibustion + MIF inhibitor ISO-1 (MOX + ISO-1) group. Rats in the ISO-1 group and ISO-1 + MOX group were intraperitoneally injected with the inhibitor ISO-1. The rats in the RA group, ISO-1 group, MOX group, and ISO-1 + MOX group were injected with Freund's complete adjuvant (FCA) in the right hind footpad to establish an experimental RA rat model. In the MOX group and MOX + ISO-1 group, rats were treated with Moxa. The thickness of the footpads of the rats in each group was measured at three-time points before, after modeling and after moxibustion treatment. The contents of serum MIF, corticosterone (CORT), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were detected by enzyme-linked immunosorbent assay; and the contents of synovial MIF were detected by Western blot. Hematoxylin-eosin (HE) staining method was used to observe the pathological changes of synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. RESULTS: Moxibustion was found to reduce the level of MIF and alleviate inflammation in RA rats in this study. In addition, after inhibiting the expression of MIF, the level of CORT increased, and the level of TNF-α decreased. Treating RA rats with inhibited MIF by moxibustion, the level of CORT was almost unchanged, but the level of TNF-α further decreased. The correlation analysis data suggested that MIF was positively related to the expression of TNF-α and negatively correlated with the expression of CORT. CONCLUSION: Reducing MIF to increase CORT and decrease TNF-α by moxibustion treatment in RA. MIF may be a factor for moxibustion to regulate the expression of CORT, but the expression of TNF-α is due to the incomplete regulation of the MIF. This study added to the body of evidence pointing to moxibustion's anti-inflammatory mechanism in the treatment of RA.

Macrophage migration inhibitory factor (MIF) predicts survival in patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common subtypes of renal cancer, with 30% of patients presenting with systemic disease at diagnosis. This aggressiveness is a consequence of the activation of epithelial-mesenchymal transition (EMT) caused by many different inducers or regulators, signaling cascades, epigenetic regulation, and the tumor environment. Alterations in EMT-related genes and transcription factors are associated with poor prognosis in ccRCC. EMT-related factors suppress E-cadherin expression and are associated with tumor progression, local invasion, and metastasis. The aim of this study was to investigate the expression levels and prognostic significance of macrophage migration inhibitory factor (MIF), ß-catenin, and E-cadherin in ccRCC patients. We examined these proteins immunohistochemically in tumor areas and adjacent normal tissues resected from patients with ccRCC. Analysis of the cancer genome atlas (TCGA) cohort was performed to verify our results. Kaplan-Meier analysis showed that median overall survival (OS) was significantly shorter in patients with tumors exhibiting high MIFn and MIFm-c levels compared to those with low MIFn and MIFm-c levels (p = 0.03 and p = 0.007, respectively). In the TCGA cohort, there was a significant correlation between MIF expression and OS (p < 0.0001). In conclusion, this study provides further evidence for the biological and prognostic value of MIF in the context of EMT as a potential early prognostic marker for advanced-stage ccRCC.

Unpacking Immune Modulation as a Site of Therapeutics Innovation for Nematode Parasite Wuchereria bancrofti: A Temporal Quantitative Phosphoproteomics Profiling of Macrophage Migration Inhibitory Factor 2.

Nematode infections are common in both humans and livestock, with major adverse planetary health and economic impacts. Wuchereria bancrofti is a parasitic nematode that causes lymphatic filariasis, a neglected tropical disease that can lead to severe disability and deformity worldwide. For the long-term survival of the bancroftian parasites in the host, a complex immune invasion strategy is involved through immunomodulation. Therefore, immunomodulation can serve as a site of research and innovation for molecular targets. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine crucial to the host antimicrobial alarm system and stress response. Interestingly, the nematode parasite W. bancrofti also produces two homologs of MIF (Wba-MIF1 and 2). Using a mass spectrometry-based phosphoproteomics approach, we report new findings on the immunomodulatory effect and signaling mechanism of Wba-MIF2 in macrophage cells. Accordingly, we observed 1201 phosphorylated sites on 467 proteins. Out of the 1201 phosphorylated sites, 1075, 117, and 9 were found on serine (S), threonine (T), and tyrosine (Y) residues, respectively. Our bioinformatics analysis led to identification of major pathways, including spliceosomes, T cell receptor signaling pathway, Th17 differentiation pathway, interleukin-17 signaling pathway, and insulin signaling pathway upon Wba-MIF2 treatment. Wba-MIF2 treatment also enriched CDK4, CDK1, and DNAPK kinases. The comparison of the signaling pathway of Wba-MIF2 with that of human-MIF suggests both share similar signaling pathways. These findings collectively offer new insights into the role and mechanism of Wba-MIF2 as an immunomodulator and inform future diagnostics and drug discovery research for W. bancrofti.

Single-cell RNA sequencing reveals the MIF-ACKR3 receptor-ligand interaction between iCAFs and tumor cells in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the gastrointestinal tract with a high morbidity and mortality rate. The heterogeneity of ESCC poses challenges in treatment and contributes to the poor prognosis of patients. Therefore, it is crucial to gain a better understanding of the tumor microenvironment (TME) heterogeneity and identify novel therapeutic targets. METHODS: To solve this problem, we performed a single-cell RNA sequencing (scRNA-seq) analysis of ESCC samples obtained from the GEO database. RESULTS: A total of 31,283 single cells were categorized into nine cell types, which included four non-immune cells (epithelial cells, endothelial cells, fibroblasts, schwann cells) and five immune cells (T cells, macrophages, mast cells, neutrophils, B cells). Our study revealed the presence of immunosuppressive tumor microenvironments in ESCC. We have also identified not only inflammatory cancer-associated fibroblast (iCAFs) and myofibroblastic cancer-associated fibroblasts (myCAFs) but also a subset of antigen presenting cancer-associated fibroblasts (apCAFs) which express high levels of HLA class II molecules in ESCC. Furthermore, our analysis of cell communication showed up-regulation of MIF-ACKR3 interaction between iCAFs and tumor cells in tumors compared to normal tissues. Finally, it was demonstrated that macrophage migration inhibitory factor (MIF) facilitates tumor cell migration and invasion through interacting with ACKR3 in vitro. CONCLUSIONS: This study exposes the features of the tumor microenvironment of ESCC via scRNA-seq and examines the dynamics of various cellular subpopulations, thus facilitating the identification of future therapeutic targets for ESCC.

Macrophage inhibitory factor alters the functionality of macrophages and their involvement in disease pathogenesis of active generalized vitiligo patients.

INTRODUCTION: In autoimmune dermatitis patients, a macrophage migration inhibitory factor (MIF) is widely used to determine the severity of the diseases with other clinical parameters. Moreover, in vitiligo, MIF has shown significant positive correlation with the VASI (Vitiligo Area Scoring Index) score of both generalized and localized vitiligo patients. MIF function as pro-inflammatory cytokine and inhibited random migration of macrophages from inflammation loci. Hence, activated macrophage infiltrates promote the diseases pathogenesis. Till date, macrophages and involvement of their secreted MIF in disease severity of vitiligo patients remains undetermined. MATERIAL AND METHOD: The frequency of both M1 and M2 macrophages was evaluated in active GV patients (n = 20) using flow cytometry in blood and in tissues by confocal microscopy (n = 10). Relative m-RNA expression and cytokine profiling of pro and anti-inflammatory mediators were estimated in PBMCs and in serum of patients. Lastly, concentration of nitric oxide and phagocytic activity from macrophages of active patients were calculated to understand the diseases pathology in detail. RESULT: Both in circulation as well as in tissues, the infiltration of M1 macrophages was increased in active GV patients, while the percentage of M2 macrophages was comparable to healthy tissues. Aberrant expression of pro and anti-inflammatory molecules including IL-1ß, IL-6, TNF-α, IL-12 and MIF impair the cellular hemostasis and induce systematic inflammation. Elevated nitric oxide and higher phagocytic activity of macrophages enhanced the destruction and/or depigmentation of melanocytes causing vitiligo. CONCLUSION: Elevated macrophages in both tissue and blood enhanced the secretion of MIF and other inflammatory mediators that further enforce the production of nitric oxide, activation and phagocytic activity of macrophages against melanocytes and melanocytes antigens. As a result, destruction of melanocytes and melanin production occurred and caused the depigmentation and/or white macules on the skin.

Macrophage migration inhibitory factor favors Neospora caninum infection in mice.

Neospora caninum is a protozoan parasite with worldwide incidence, acting as a major cause of reproductive failures in ruminants and neuromuscular symptoms in dogs. Macrophage Migration Inhibitory Factor (MIF) is produced by several cell types and exhibits a central role in immune responses against intracellular pathogens. The present study aimed to comprehend the role of MIF in the relationship between N. caninum and its host. We used in vivo, in vitro and ex vivo experiments in a model of infection based on genetically deficient mice to analyze the infection kinetics and inflammatory markers. MIF production was measured in response to N. caninum during the acute and chronic phases of the infection. While Mif-/- mice survived lethal doses of NcLiv tachyzoites, sublethal infections in these mice showed that parasite burden was controlled in target tissues, alongside with reduced inflammatory infiltrates detected in lung and brain sections. TNF was increased at the initial site of the infection in genetically deficient mice and the MIF-dependent reduction was confirmed in vitro with macrophages and ex vivo with primed spleen cells. In sum, MIF negatively regulated host immunity against N. caninum, favoring disease progression.

Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition.

Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society.

Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming That Drives Immune Evasion.

Reprogramming of energy metabolism exerts pivotal functions in cancer progression and immune surveillance. Identification of the mechanisms mediating metabolic changes in cancer may lead to improved strategies to suppress tumor growth and stimulate antitumor immunity. Here, it was observed that the secretomes of hypoxic breast cancer cells and breast cancer stem cells (BCSC) induced reprogramming of metabolic pathways, particularly glycolysis, in normoxic breast cancer cells. Screening of the BCSC secretome identified MIF as a pivotal factor potentiating glycolysis. Mechanistically, MIF increased c-MYC-mediated transcriptional upregulation of the glycolytic enzyme aldolase C by activating WNT/ß-catenin signaling. Targeting MIF attenuated glycolysis and impaired xenograft growth and metastasis. MIF depletion in breast cancer cells also augmented intratumoral cytolytic CD8+ T cells and proinflammatory macrophages while decreasing regulatory T cells and tumor-associated neutrophils in the tumor microenvironment. Consequently, targeting MIF improved the therapeutic efficacy of immune checkpoint blockade in triple-negative breast cancer. Collectively, this study proposes MIF as an attractive therapeutic target to circumvent metabolic reprogramming and immunosuppression in breast cancer. SIGNIFICANCE: MIF secreted by breast cancer stem cells induces metabolic reprogramming in bulk tumor cells and engenders an immunosuppressive microenvironment, identifying MIF targeting as a strategy to improve immunotherapy efficacy in breast cancer.

Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti.

Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.

Murine double minute 2-mediated estrogen receptor 1 degradation activates macrophage migration inhibitory factor to promote vascular smooth muscle cell dedifferentiation and oxidative stress during thoracic aortic aneurysm progression.

Estrogen receptor 1 (ESR1) has been recently demonstrated as a potential diagnostic biomarker for thoracic aortic aneurysm (TAA). However, its precise role in the progression of TAA remains unclear. In this study, TAA models were established in ApoE-knockout mice and primary mouse vascular smooth muscle cells (VSMCs) through treatment with angiotensin (Ang) II. Our findings revealed a downregulation of ESR1 in Ang II-induced TAA mice and VSMCs. Upregulation of ESR1 mitigated expansion and cell apoptosis in the mouse aorta, reduced pathogenetic transformation of VSMCs, and reduced inflammatory infiltration and oxidative stress both in vitro and in vivo. Furthermore, we identified macrophage migration inhibitory factor (MIF) as a biological target of ESR1. ESR1 bound to the MIF promoter to suppress its transcription. Artificial MIF restoration negated the mitigating effects of ESR1 on TAA. Additionally, we discovered that murine double minute 2 (MDM2) was highly expressed in TAA models and mediated protein degradation of ESR1 through ubiquitination modification. Silencing of MDM2 reduced VSMC dedifferentiation and suppressed oxidative stress. However, these effects were reversed upon further silencing of ESR1. In conclusion, this study demonstrates that MDM2 activates MIF by mediating ESR1 degradation, thus promoting VSMC dedifferentiation and oxidative stress during TAA progression.

Sulforaphane effectively inhibits HBV by altering Treg/Th17 immune balance and the MIF-macrophages polarizing axis in vitro and in vivo.

BACKGROUND: Hepatitis B virus (HBV) infection is a major public health problem. After HBV infection, viral antigens shift the immune balance in favor of viral escape. Sulforaphane (SFN) is a traditional Chinese medicine.It regulates multi-biological activities, including anti-inflammation, anticancer, and antiviral. However, few studies reported that SFN can inhibit HBV infection before. METHODS: An immunocompetent HBV CBA/CaJ mouse model and a co-culture model were used to explore the effect of SFN on HBV and whether SFN altered the immune balance after HBV infection. RESULTS: We found that SFN was able to reduce HBV DNA, cccDNA, HBsAg, HBeAg, and HBcAg levels in serum and liver tissues of HBV-infected mice. In vitro and in vivo experiments showed that SFN could significantly increase the expression of Cd86 and iNOS and inhibit the expression of Arg1 on macrophages after HBV infection. After SFN administration, Th17 markers in liver tissue and serum were significantly increased. There was no significant changes in the proportion of Treg cells in peripheral blood, but a significant increase in the proportion of Th17 cells and decrease of the Treg/Th17 ratio. Using a network pharmacology approach, we predicted macrophage migration inhibitory factor (MIF) as a potential target of SFN and further validated that MIF expression was significantly increased after HBV infection and SFN significantly inhibited MIF expression both in vitro and in vivo. There was an upward trend in HBV markers (p>0.05) after MIF overexpression. Overexpression of MIF combined with the use of SFN resulted in a significant reversion in the expression of HBV markers and polarization of macrophages towards the M1 phenotype. CONCLUSION: Our results indicated that immunocompetent HBV CBA/CaJ mouse model is a good model to evaluate HBV infection. SFN could inhibit the expression of HBV markers, promote polarization of macrophages towards the M1 phenotype after HBV infection, change the proportion of Treg and Th17 cells. Our findings demonstrate that SFN inhibit HBV infection by inhibiting the expression of MIF and promoting the polarization of macrophages towards the M1 phenotype, which illustrates a promising therapeutic approach in HBV infection.

High temperature requirement A1 and macrophage migration inhibitory factor in the cerebrospinal fluid; a potential marker of conversion from relapsing-remitting to secondary progressive multiple sclerosis.

BACKGROUND: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). OBJECTIVE: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. METHODS: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. RESULTS: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. CONCLUSION: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.

A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation.

Macrophage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress.

Genetic Evidence for the Causal Association of Circulating Cytokines and Growth Factors With Coronary Artery Disease.

BACKGROUND: Observational studies have suggested the potential role of inflammatory factors in the risk of coronary artery disease (CAD). We aimed to perform 2-sample Mendelian randomization (MR) analyses to assess the causal association between circulating cytokines/growth factors and CAD. METHODS AND RESULTS: The instrumental variables for 28 circulating cytokines and growth factors were identified from a genome-wide association study of 8293 European participants. Summary-level data on CAD were derived from a large genome-wide association study (71 602 cases and 260 875 controls). We used the inverse-variance-weighted and Wald ratio methods as our main MR methods. The weighted median, simple median, maximum likelihood, MR pleiotropy residual sum and outlier, and MR-Egger methods were performed as sensitivity analyses. Genetic colocalization analyses were conducted to validate the robustness of our MR findings. We found that genetically predicted circulating levels of macrophage migration inhibitory factor were associated with an increased risk of CAD at the Bonferroni-adjusted level of significance (P<1.79×10-3). The odds ratio was 1.20 (95% CI, 1.08-1.33; P=6.83×10-4) per 1-SD increase in macrophage migration inhibitory factor. Colocalization analyses supported our MR findings. Additionally, we found suggestive evidence between the genetic effects of stem cell growth factor-ß and the risk of CAD (odds ratio, 0.95 [95% CI, 0.91-0.98]; P=0.007). CONCLUSIONS: Our findings suggested a risk-increasing effect of macrophage migration inhibitory factor level on the development of CAD. The roles of these inflammatory factors for CAD warrant further investigation.

MIF contribution to progressive brain diseases.

Progressive brain diseases create a huge social and economic burden on modern societies as a major cause of disability and death. Incidence of brain diseases has a significantly increasing trend and merits new therapeutic strategies. At the base of many progressive brain malfunctions is a process of unresolved, chronic inflammation. Macrophage migration inhibitory factor, MIF, is an inflammatory mediator that recently gained interest of neuro-researchers due to its varied effects on the CNS such as participation of nervous system development, neuroendocrine functions, and modulation of neuroinflammation. MIF appears to be a candidate as a new biomarker and target of novel therapeutics against numerous neurologic diseases ranging from cancer, autoimmune diseases, vascular diseases, neurodegenerative pathology to psychiatric disorders. In this review, we will focus on MIF's crucial role in neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and glioblastoma (GBM).

Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population.

BACKGROUND: More than 800 000 people die by suicide annually. The heritability of suicide is 30%-50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia-inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single-nucleotide polymorphism (SNP), in suicide completers and controls. METHODS: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). RESULTS: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. CONCLUSION: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF-related genetic studies, including those of rs17004038, are necessary with larger sample sizes.

Obesity-related Plasma CXCL10 Drives CX3CR1-dependent Monocytic Secretion of Macrophage Migration Inhibitory Factor.

Obesity is characterized by excessive body fat accumulation and comorbidities such as diabetes mellitus, cardiovascular disease, and obstructive sleep apnea syndrome (OSAS). Both obesity and OSAS are associated with immune disturbance, alterations of systemic inflammatory mediators, and immune cell recruitment to metabolic tissues. Chemokine CXCL10 is an important regulator of proinflammatory immune responses and is significantly increased in patients with severe obesity. This research project aims to investigate the impact of CXCL10 on human monocytes in patients with obesity. We studied the distribution of the CD14/CD16 monocyte subsets as well as their CX3CR1 expression patterns in whole-blood measurements from 92 patients with obesity and/or OSAS with regard to plasma CXCL10 values and individual clinical parameters. Furthermore, cytokine secretion by THP-1 monocytes in response to CXCL10 was analyzed. Data revealed significantly elevated plasma CXCL10 in patients with obesity with an additive effect of OSAS. CXCL10 was found to drive monocytic secretion of macrophage migration inhibitory factor via receptor protein CX3CR1, which significantly correlated with the individual body mass index. Our data show, for the first time, to our knowledge, that CX3CR1 is involved in alternative CXCL10 signaling in human monocytes in obesity-related inflammation. Obesity is a multifactorial disease, and further investigations regarding the complex interplay between obesity-related inflammatory mediators and systemic immune balances will help to better understand and improve the individual situation of our patients.