Plasma Macrophage Migration Inhibitory Factor Research Articles

Macrophage Migration Inhibitory Factor Promotes Thromboinflammation and Predicts Fast Progression of Aortic Stenosis.

Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

High circulating MIF levels indicate the association with atypical antipsychotic-induced adverse metabolic effects.

Atypical antipsychotics (AAPs) are primary medications for schizophrenia (SZ). However, their use is frequently associated with the development of adverse metabolic effects, and the mechanisms behind these negative effects remain inadequately elucidated. To investigate the role of macrophage migration inhibitory factor (MIF) in regulating antipsychotic-induced metabolic abnormalities, between 2017 and 2020, a cross-sectional study was conducted, involving 142 healthy individuals and 388 SZ patients undergoing treatment with either typical antipsychotic (TAP) or AAP medications. Symptoms of SZ patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), and measurements of metabolic indices and plasma MIF levels were performed on all individuals. A significant increase in plasma MIF levels was observed in groups receiving five major AAP monotherapies in comparison to healthy controls (all p < 0.0001). There was no such increase shown in the group receiving TAP treatment (p > 0.05). Elevated plasma MIF levels displayed a notable correlation with insulin resistance (β = 0.024, p = 0.020), as well as with the levels of triglycerides (β = 0.019, p = 0.001) and total cholesterol (β = 0.012, p = 0.038) in the groups receiving AAPs. However, while the TAP group also displayed certain metabolic dysfunction compared to healthy controls, no significant association was evident with plasma MIF levels (all p > 0.05). In conclusion, plasma MIF levels exhibit a distinctive correlation with metabolic abnormalities triggered by AAPs. Hence, there is potential for further development of MIF as a distinctive marker for monitoring adverse metabolic effects induced by AAPs in clinical settings.

Effect of Leptin Receptor Q223R Polymorphism on Clostridioides difficile Infection-Induced Macrophage Migration Inhibitory Factor Production.

Proinflammatory cytokine levels and host genetic makeup are key determinants of Clostridioides difficile infection (CDI) outcomes. We previously reported that blocking the inflammatory cytokine macrophage migration inhibitory factor (MIF) ameliorates CDI. Here, we determined kinetics of MIF production and its association with a common genetic variant in leptin receptor (LEPR) using blood from patients with CDI. We found highest plasma MIF early after C difficile exposure and in individuals who express mutant/derived LEPR. Our data suggest that early-phase CDI provides a possible window of opportunity in which MIF targeting, potentially in combination with LEPR genotype, could have therapeutic utility.

Integrin CD11c regulates B cell homeostasis.

CD11c is widely known as a cell surface marker for dendritic cells, but we recently showed that it regulates neutrophil and T cell functions. Because we found that CD11c knockout (KO) mice had lower blood B cell counts, we characterized B cell profile in developmental stages. We found that CD11c KO recirculating and mature B cells was significantly fewer compared with wild type, associated with exaggerated proliferation and apoptosis. Because they did not express CD11c, we sought for the possibility of CD11c-mediated non-intrinsic regulation of B cell proliferation and apoptosis. Here we hypothesized that dendritic cells, major cells expressing CD11c would regulate B cells indirectly. The proteomics of dendritic cells cultured in vitro indicated the downregulation of macrophage migration inhibitory factor (MIF). Less MIF was also confirmed by ELISA. Furthermore, plasma MIF level was significantly lower in naïve CD11c KO mice. Because MIF regulates B cell survival, we demonstrated a novel regulatory mechanism of naïve B cells via CD11c.

Subjective Assessment Underestimates Fraility in Patients With Heart Failure Referred for Advanced Therapies.

Assessment of frailty is key for evaluation for advanced therapies (ATs). Most programs use a subjective provider assessment (SPA) or "eye-ball" test; however, objective measures exist. The modified five-item Fried Frailty Index (mFFI) is a validated tool to assess frailty. We compared SPA to mFFI testing in patients referred for AT. We also compared levels of macrophage migration inhibitory factor (MIF), an inflammatory biomarker associated with worse outcomes in heart failure, between frail and not frail subjects. Seventy-eight patients referred for evaluation for AT underwent both SPA and mFFI testing. Three cardiac surgeons independently assessed patients for frailty (SPA). SPA significantly underestimated frailty compared with mFFI testing and correlation between SPA and mFFI was not strong (κ = 0.02-0.14). Providers were correct 84% of the time designating a subject as frail, but only 40% of the time designating as not frail. Agreement between all three providers was robust (76%), which was primarily driven by designation as not frail. There was no significant difference in plasma MIF levels between frail and not frail subjects (47.6 ± 25.2 vs . 45.2 ± 18.9 ng/ml; p = 0.6). Clinicians significantly underestimate frailty but are usually correct when designating a patient as frail.

ДИАГНОСТИЧЕСКАЯ ЦЕННОСТЬ ОПРЕДЕЛЕНИЯ ЦИТОКИНА MIF В КОМБИНАЦИИ С ПАРАМЕТРАМИ ОБЩЕГО АНАЛИЗА КРОВИ ДЛЯ ОЦЕНКИ СТЕРОИДОРЕЗИСТЕНТНОСТИ ПРИ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХ

Based on the results of previous work, we have proposed two mathematical models to predict the low effectiveness of glucocorticoids in patients hospitalized for treatment of exacerbation of chronic obstructive pulmonary disease (COPD). The aim of this study was to compare their characteristics. In total, 28 COPD patients who were admitted to hospital due to exacerbations were included in this study. Determination of the regression equation, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and eosinophil count in the blood of examination group of patients showed high diagnostic efficiency (78.6%), sensitivity (81.8%) and specificity (76.5%) of the mathematical model. Another model, which includes blood eosinophil count, PLR and MIF (macrophage migration inhibitory factor) level, had diagnostic efficiency of 85.7%, sensitivity of 81.8%, and specificity of 88.2%. The first model, which includes only parameters of complete blood count, can be calculated after the initial examination by the attending physician. The second model, which requires the determination of blood plasma MIF level by enzyme-linked immunosorbent assay and, accordingly, more time, but has higher efficiency and specificity, should be used after a second examination by the attending physician.

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.

Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection.

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1β and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

Difference in macrophage migration inhibitory factor between preterm and term newborns and associating clinical factors: Preliminary study.

This study aimed to investigate the macrophage migration inhibitory factor (MIF) and associated clinical factors in neonates. Clinical information and blood samples were obtained from 77 neonates. Clinical details were reviewed from medical records, and MIF was measured by enzyme-linked immunosorbent assay using blood samples acquired within a week after birth. Statistical analyses were performed between plasma MIF concentration and clinical factors. Among the 77 newborn infants, 25 were born at <34 weeks of gestation (preterm), 25 at 34 to 37 weeks (late preterm), and 27 at term gestation. The mean MIF was 9849.5 ± 7187.8 pg/mL in preterm, 5718.7 ± 4596.4 in late preterm, and 5361.1 ± 3895.7 in term infants (P = .016). Among 25 preterm infants born at <34 weeks of gestation, MIF was significantly higher in infants with necrotizing enterocolitis (NEC, 19,478.6 ± 8162.4 pg/mL, n = 5) than that in infants without NEC (feeding intolerance 7173.7 ± 4203.0 pg/mL, n = 12 and others 7844.9 ± 5311.2 pg/mL, n = 8, P = .020). Elevated plasma MIF levels in the transitional period were significantly associated with preterm birth before 34 weeks of gestation and the development of NEC.

CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis

Type 2 diabetes mellitus (T2D) contributes to sustained inflammation and myopathic changes in the heart although the precise interplay between the two remains largely unknown. This study evaluated the impact of deficiency in CD74, the cognate receptor for the regulatory cytokine macrophage migration inhibitory factor (MIF), in T2D-induced cardiac remodeling and functional responses, and cell death domains involved. WT and CD74-/- mice were fed a high fat diet (60% calorie from fat) for 8 weeks prior to injection of streptozotocin (STZ, 35 mg/kg, i.p., 3 consecutive days) and were maintained for another 8 weeks. KEGG analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis in T2D mouse hearts. T2D patients displayed elevated plasma MIF levels. Murine T2D exerted overt global metabolic derangements, cardiac remodeling, contractile dysfunction, apoptosis, pyroptosis, ferroptosis and mitochondrial dysfunction, ablation of CD74 attenuated T2D-induced cardiac remodeling, contractile dysfunction, various forms of cell death and mitochondrial defects without affecting global metabolic defects. CD74 ablation rescued T2D-evoked NLRP3-Caspase1 activation and oxidative stress but not dampened autophagy. In vitro evidence depicted that high glucose/high fat (HGHF) compromised cardiomyocyte function and promoted lipid peroxidation, the effects were ablated by inhibitors of NLRP3, pyroptosis, and ferroptosis but not by the mitochondrial targeted antioxidant mitoQ. Recombinant MIF mimicked HGHF-induced lipid peroxidation, GSH depletion and ferroptosis, the effects of which were reversed by inhibitors of MIF, NLRP3 and pyroptosis. Taken together, these data suggest that CD74 ablation protects against T2D-induced cardiac remodeling and contractile dysfunction through NLRP3/pyroptosis-mediated regulation of ferroptosis.

Macrophage migration inhibitory factor in Nodding syndrome.

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

Plasma Macrophage Migration Inhibitory Factor Predicts Graft Function Following Kidney Transplantation: A Prospective Cohort Study.

Background: Delayed graft function (DGF) is a common complication after kidney transplantation (KT) with a poor clinical outcome. There are no accurate biomarkers for the early prediction of DGF. Macrophage migration inhibitory factor (MIF) release during surgery plays a key role in protecting the kidney, and may be a potential biomarker for predicting post-transplant renal allograft recovery.Methods: Recipients who underwent KT between July 2020 and December 2020 were enrolled in the study. Plasma MIF levels were tested in recipients at different time points, and the correlation between plasma MIF and DGF in recipients was evaluated. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000035596).Results: Intraoperative MIF levels were different between immediate, slowed, and delayed graft function groups (7.26 vs. 6.49 and 5.59, P < 0.001). Plasma MIF was an independent protective factor of DGF (odds ratio = 0.447, 95% confidence interval [CI] 0.264–0.754, P = 0.003). Combining plasma MIF level and donor terminal serum creatinine provided the best predictive power for DGF (0.872; 95%CI 0.795–0.949). Furthermore, plasma MIF was significantly associated with allograft function at 1-month post-transplant (R2 = 0.42, P < 0.001).Conclusion: Intraoperative MIF, as an independent protective factor for DGF, has excellent diagnostic performance for predicting DGF and is worthy of further exploration.

197-LB: The Regulation of HSL by Macrophage Migration Inhibitory Factor (MIF) Contributes to Adipocyte Hypertrophy and Development of Obesity

Inflammation is associated with lipolysis in adipose tissue. HSL is a key enzyme in mediating lipolysis through augmenting hydrolysis of triglycerides and diacylglycerides. Our study found that the procytokine MIF has both transcriptional and non-transcriptional effects on mediating HSL through activating AMPK signaling pathway. The activated AMPK downregulates HSL gene expression in adipocytes. It also upregulates a phosphorylation of HSL Ser565, an inhibitory phosphorylation site, leading to the reduction of HSL active site, Ser563 phosphorylation. These mechanisms are operative in either transgenic overexpressed MIF mouse models or WT mice with high circulating MIF levels following a high caloric diet feeding (HFD). The MIF/AMPK/HSL axis regulates the development of adipocyte hypertrophy and obesity. We also confirm that high plasma MIF levels are associated with decreased adipose HSL gene expression in human obesity. Interestingly, in Mif-/-mice, HSL gene expression is also inhibited, suggesting that MIF genotype is important to maintain adipose HSL expression. Following HFD feeding, Mif-/-mice demonstrates higher Akt and lower PKA phosphorylation, which further decrease HSL activation and exacerbate obesity compared to WT. Thus, HSL regulation by MIF may be an important molecular mechanism in the development of obesity.View largeDownload slideView largeDownload slide DisclosureL. Chen: None. Y. Huang: None. L. Li: None. H. Zabihi: None. Y. Qi: None. L. Leng: None. G. Sun: None. R. Bucala: None. D. Qi: None.FundingNational Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); Canadian Institutes of Health Research (PJT-156116)

Macrophage Migration Inhibitory Factor (MIF) Plasma Concentration in Critically Ill COVID-19 Patients: A Prospective Observational Study.

Mortality in critically ill coronavirus disease 2019 (COVID-19) patients is high and pharmacological treatment strategies remain limited. Early-stage predictive biomarkers are needed to identify patients with a high risk of severe clinical courses and to stratify treatment strategies. Macrophage migration inhibitory factor (MIF) was previously described as a potential predictor for the outcome of critically ill patients and for acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19 disease. This prospective observational study evaluates the predictive potential of MIF for the clinical outcome after severe COVID-19 infection. Plasma MIF concentrations were measured in 36 mechanically ventilated COVID-19 patients over three days after intensive care unit (ICU) admission. Increased compared to decreased MIF was significantly associated with aggravated organ function and a significantly lower 28-day survival (sequential organ failure assessment (SOFA) score; 8.2 ± 4.5 to 14.3 ± 3, p = 0.009 vs. 8.9 ± 1.9 to 12 ± 2, p = 0.296; survival: 56% vs. 93%; p = 0.003). Arterial hypertension was the predominant comorbidity in 85% of patients with increasing MIF concentrations (vs. decreasing MIF: 39%; p = 0.015). Without reaching significance, more patients with decreasing MIF were able to improve their ARDS status (p = 0.142). The identified association between an early MIF response, aggravation of organ function and 28-day survival may open future perspectives for biomarker-based diagnostic approaches for ICU management of COVID-19 patients.

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.

Estimation of the level of macrophage migration inhibitory factor in patients with coronary artery disease in the presence of some risk factors

Background and objective: Coronary artery disease is a chronic inflammatory disease in which many risk factors and inflammatory mediators, including macrophage migration inhibitory factor, are involved. This study aimed to estimate macrophage migration inhibitory factor level in coronary artery disease patients in regard to age, gender, and smoking. Methods: A total of 138 coronary artery disease patients and 38 coronary artery disease free control subjects were admitted to surgical specialty hospital-cardiac center in Erbil city, Iraq between January and December 2017. Plasma macrophage migration inhibitory factor concentration was measured by enzyme linked immunosorbent assay. Results: Patients and controls were categorized into subgroups according to age (&lt;55 and ≥55 years), gender (women and men), and smoking status (smokers and non-smokers). Macrophage migration inhibitory factor level in every coronary artery disease subgroup (age, gender, and smokers) patients increased significantly compared to the same control subgroups (P &lt;0.05). Macrophage migration inhibitory factor level showed a higher level in coronary artery disease patients subgroups (≥55 years, female, smokers) compared to their corresponding coronary artery disease subgroups (&lt;55 years, male, and non smokers). Macrophage migration inhibitory factor demonstrated a significant positive correlation with fibrinogen and high sensitivity C-reactive protein, insignificant positive correlation with age, total cholesterol, low density lipoprotein, and insignificant negative correlation with high density lipoprotein-cholesterol (P &gt;0.05). Conclusion: This study demonstrated the diagnostic value of macrophage migration inhibitory factor elevation in coronary artery disease patients if compared with coronary artery disease free subjects, meanwhile suggesting that age, gender, and smoking had no direct role in macrophage migration inhibitory factor elevation considering their secondary minor contributions in macrophage migration inhibitory factor circulation. Keywords: Coronary; Macrophage; Age; Gender; Smoking.

44-OR: PAR2-Regulated MIF Secretion from Non-Immune Cells in Adipose Tissue Is a Key Mechanism Involved in the Development of Metabolic Dysfunction

Macrophage migration inhibitory factor (MIF) is a cytokine that is increased in obesity and contributes to metabolic dysfunction. Our present study describes a novel mechanism by which fatty acids activate non-immune cells to increase MIF secretion in adipose tissue, initiating cross-talk between preadipocytes and adipocytes. High fatty acids specifically induce protease-activated receptor 2 (PAR2) activation in preadipocytes, which downregulates pref-1 expression and release. Preadipocyte factor 1 (Pref-1) has an autocrine-paracrine action to inhibit the release of MIF from both preadipocytes and adipocytes. Thus, the loss of Pref-1 secretion during high fat feeding is responsible in part for both increased MIF secretion in adipose tissue and the rise in plasma MIF levels that ensues. The physiological consequences are most evident in adipose tissue. Genetic deletion of Par2 confirms the importance of this mechanism in mice, protecting against high fat diet-induced metabolic dysfunction. Importantly, this novel mechanism is also operative in adipose tissue from obese human subjects. These results provide the scientific rationale to consider whether strategies to either block Par2 expression or augment Pref-1 secretion might improve metabolic health in obesity or type 2 diabetes. Disclosure Y. Huang: None. L. Chen: None. Y. Qi: None. D. Qi: None.

Macrophage Migration Inhibitory Factor as a Predictor for Long-term Improvements After Mindfulness-Based Group Therapy or Treatment as Usual for Depression, Anxiety or Stress and Adjustment Disorders

ObjectivesIdentification of biological markers that can guide treatment selection is considered to be a viable solution for personalized treatment for patients with psychiatric disorders. This study investigated whether macrophage migration inhibitory factor (MIF) levels at baseline were associated with mindfulness-based group therapy or cognitive behavioral therapy response in patients with mild to moderate symptoms of depression, anxiety, or stress- and adjustment disorders.MethodsA total of 168 patients (aged 21–65 years) with psychiatric disorders were included from a randomized controlled trial. Plasma MIF levels in all the patients were analyzed using Luminex assay.ResultsHigher MIF levels at baseline were significantly associated with better long-term (1-year follow-up) improvement in psychiatric symptoms, as measured by changes in the Montgomery-Åsberg Depression Rating Scale (MADRS-S), compared with lower MIF levels, after adjustment for baseline MADRS-S score, age, sex, BMI, and pharmacotherapy (β = 5.89, p = 0.001). Patients with higher levels of MIF (8235–23,391 pg/ml) had an almost 6 points’ larger decrease in MADRS-S score after 1 year compared with those with lower MIF (727–8223 pg/ml) at baseline. Similar trends were seen after 8 weeks, albeit non-significant (β = 1.99, p = 0.18).ConclusionsThe findings indicate that higher plasma MIF levels at baseline may predict better long-term outcomes with psychotherapeutic interventions for mild to moderate symptoms of depression, anxiety, or stress and adjustment disorders. MIF levels may serve as a potential biomarker that can guide treatment selection for the personalized treatment for patients with psychiatric disorders.

MIF gene rs755622 polymorphism positively associated with acute coronary syndrome in Chinese Han population: case\u2013control study

Macrophage migration inhibitory factor (MIF) has been recognized as a major player in the pathogenesis of atherosclerosis. This study determined the association between polymorphisms of MIF gene and acute coronary syndrome (ACS). The polymorphism of MIF gene (rs755622, rs1007888 and rs2096525) was analyzed in 1153 healthy controls and 699 ACS cases in Chinese Han population. Plasma MIF level was also measured in part of ACS patients (139/19.9%) and healthy controls (129/11.2%) randomly. Most participants including healthy controls and ACS patients carried rs755622 GG (63.1% vs. 56.7%) and CG genotypes (33.1% vs. 38.9%) and G allele of rs755622 (79.6% vs. 76.1%, respectively), while CC genotype (3.8% vs. 4.4%) and C allele (20.4% vs. 23.9%) carriers were the lowest. Multivariate logistic regression analysis showed that carriers with rs755622 C allele had a higher risk of ACS compared to other genotypes (AOR = 1.278, 95% CI: 1.042–1.567). In addition, CC genotype carriers had the highest plasma levels of MIF than other genotype carriers. The MIF level in ACS patients with CC genotype was significantly higher than ACS patients carrying GG genotype and healthy controls carrying 3 different genotypes of MIF gene rs755622. Our findings indicate that MIF gene rs755622 variant C allele is associated with increased risk of ACS. Identification of this MIF gene polymorphism may help for predicting the risk of ACS.