Macrophage Migration Inhibitory Factor deficiency attenuates kidney Injury by downregulating cytokines via CYR61 in lupus-prone mice induced by pristane.

Abstract Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematous (SLE) and accounts for significant mortality and morbidity. Previous research has demonstrated that macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of lupus nephritis, but the detailed mechanism is not elucidated. The aim of this study was to explore the pathogenesis of MIF in lupus nephritis with the pristane-induced mouse model of SLE. Methods Mif-/- mice and Wild type mice in the C57BL/6 (B6) background were used to induce Lupus model by pristane. 24 hour urine and sera were collected in the sixth month and mice were sacrificed to harvest tissues. Serum ANA, anti-dsDNA antibodies, C3, urinary creatinine and albumin were detected by ELISA. Related inflammatory cytokines were detected by Bio-Plex Pro™ assays and ELISA. CYR61 mRNA expression was detected by RT-qPCR and CYR61 protein expression were detected by Western blot. Immunofluorescence was used to detect the expression of MIF, ICs and C3 deposition and related cytokines expression in the kidneys. Immunohistochemical staining was used to detect macrophage infiltration and periodic acid-Schiff (PAS) staining were used for kidney histology. The Mann-Whitney test and Student’s t test were used to compare multiple group differences. The correlation were analyzed by Spearman correlation. Results Mif -/- mice with pristane-induced SLE have less inflammatory cytokines expression in sera. The Mif-/- mice have reduced renal injury, less macrophage infiltration, CYR61 and inflammatory cytokines expression in the kidneys. MIF induced the expression of CYR61, which can induce the expression of IL-1β, IL-6 and MCP-1 in bone marrow-derived macrophages (BMDM) in a cell-based assay. Conclusions The results suggest that MIF plays an important role in kidney injury by inducing macrophages infiltration and inflammatory cytokines expression in situ. Our finding support the pathogenic contribution of high expression MIF alleles in SLE and suggest that MIF antagonism might offer an effective therapeutic option in lupus nephritis.

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FRI0430 Association Between Circulating Macrophage Migration Inhibitory Factor (MIF) with Adipokines Levels, Auto-Antibodies and Pro-Inflammatory Cytokines in Lupus Nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-eular.5881 ◽

2015 ◽

Vol 74 (Suppl 2) ◽

pp. 582.2-583 ◽

Cited By ~ 1

Author(s):

V. Diaz Rizo ◽

N.S. Fajardo Robledo ◽

J.D. Murillo Vazquez ◽

E. Perez Guerrero ◽

X. Trujillo ◽

...

Keyword(s):

Lupus Nephritis ◽

Inflammatory Cytokines ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Pro Inflammatory Cytokines

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Pro- and Anti-Inflammatory Properties of Interleukin in Vitro: Relevance for Major Depression and Human Hippocampal Neurogenesis

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa055 ◽

2020 ◽

Vol 23 (11) ◽

pp. 738-750

Author(s):

Alessandra Borsini ◽

Maria Grazia Di Benedetto ◽

Juliette Giacobbe ◽

Carmine M Pariante

Keyword(s):

Inflammatory Cytokines ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Healthy Individuals ◽

Depressed Patients ◽

Anti Inflammatory ◽

High Concentrations ◽

Very High

Abstract Background Although the pro-inflammatory cytokine interleukin (IL)6 has been generally regarded as “depressogenic,” recent research has started to question this assumption in light of the fact that this cytokine can also have anti-inflammatory properties. This bimodal action seems to be dependent on its concentration levels and on the concomitant presence of other pro-inflammatory cytokines. Methods We exposed a human hippocampal progenitor cell line, HPC0A07/03C, to cytokine levels described in depressed patients (IL6 5 pg/mL with IL1β 10 pg/mL or Macrophage Migration Inhibitory Factor (300 pg/mL) in healthy individuals (IL6 with IL1β, 1 pg/mL or Macrophage Migration Inhibitory Factor 10 pg/mL), as well as to the potentially anti-inflammatory, much higher concentrations of IL6 (50 000 pg/mL). Results Treatment with high concentrations of IL6 with IL1β or Macrophage Migration Inhibitory Factor (resembling depressed patients) decreases neurogenesis compared with low concentrations of the same cytokines (healthy individuals) and that this is mediated via production of, respectively, IL8 and IL1β in cell supernatant. Instead, treatment with very high, anti-inflammatory concentration of IL6 (50 000 pg/mL) together with high IL1β or Macrophage Migration Inhibitory Factor prevents decrease in neurogenesis and reduces both IL8 and IL1β. When high concentrations of both IL1β and Macrophage Migration Inhibitory Factor were used in co-treatment, as a model of treatment-resistant depression, we also demonstrated a reduction in neurogenesis and that this is mediated via a decrease in IL4; moreover, co-treatment with high IL1β and Macrophage Migration Inhibitory Factor and the very high concentration of IL6 prevented the reduction in neurogenesis and increased IL4. Conclusions Our results demonstrate that IL6 can exert both pro- and anti-inflammatory (potentially antidepressant) properties, depending on its concentrations and combinations with other inflammatory cytokines.

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The Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms (rs3063368, rs755622) Predict Acute Kidney Injury and Death after Cardiac Surgery

Journal of Clinical Medicine ◽

10.3390/jcm9092936 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2936

Author(s):

Luisa Averdunk ◽

Jürgen Bernhagen ◽

Karl Fehnle ◽

Harald Surowy ◽

Hermann-Josef Lüdecke ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Elevated Serum ◽

Kidney Injury ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms ◽

Risk Of Death

Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT5–7 (rs5844572/rs3063368,“-794”) and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT7) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40–2.88), p = 0.0001). Carriers of CATT7 were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99–33.14), p = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20–2.43), p = 0.003). Multivariate analyses identified CATT7 predictive for AKI (OR 2.13 (1.46–3.09), p < 0.001) and death (OR 5.58 (1.29–24.04), p = 0.021). CATT7 was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT7 allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.

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