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1.
J Pathol Clin Res ; 10(2): e12365, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38436543

RESUMO

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.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Fatores Inibidores da Migração de Macrófagos , Humanos , Carcinoma de Células Renais/genética , Fatores Inibidores da Migração de Macrófagos/genética , Epigênese Genética , Neoplasias Renais/genética , Caderinas , Oxirredutases Intramoleculares/genética
2.
Int J Mol Sci ; 25(3)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38339125

RESUMO

The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD.


Assuntos
Cardiomiopatias , Oxirredutases Intramoleculares , Lipocalinas , Distrofia Muscular de Duchenne , Animais , Humanos , Camundongos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Modelos Animais de Doenças , Mastócitos/metabolismo , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Miocárdio/metabolismo , Pericitos/metabolismo
3.
Acta Trop ; 252: 107142, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331083

RESUMO

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.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Filarioidea , Fatores Inibidores da Migração de Macrófagos , Parasitos , Humanos , Animais , Camundongos , Wuchereria bancrofti , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Parasitos/metabolismo , Estreptozocina , Fatores Imunológicos , Diabetes Mellitus Experimental/genética , Anti-Inflamatórios , Oxirredutases Intramoleculares
4.
Cell Signal ; 117: 111093, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38336189

RESUMO

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.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Fatores Inibidores da Migração de Macrófagos , Análise da Expressão Gênica de Célula Única , Humanos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Oxirredutases Intramoleculares , Ligantes , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Análise de Sequência de RNA , Microambiente Tumoral
5.
J Neuroinflammation ; 21(1): 8, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178143

RESUMO

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).


Assuntos
Encefalopatias , Fatores Inibidores da Migração de Macrófagos , Esclerose Múltipla , Doenças do Sistema Nervoso , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Inflamação , Calgranulina A , Calgranulina B , Oxirredutases Intramoleculares
6.
Oral Oncol ; 148: 106654, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38061122

RESUMO

BACKGROUND: The mechanism promoting papillary thyroid carcinoma (PTC) metastasis remains unclear. We aimed to investigate the potential metastatic mechanisms at a single-cell resolution. METHODS: We performed single-cell RNA-seq (scRNA-seq) profiling of thyroid tumour (TT), adjacent normal thyroid (NT) and lymph node metastasized tumour (LN) from a young female with PTC. Validation of our results was conducted in 31 tumours with metastasis and 30 without metastasis. RESULTS: ScRNA-seq analysis generated data on 38,215 genes and 0.14 billion transcripts from 28,839 cells, classified into 18 clusters, each annotated to represent 10 cell types. PTC cells were found to originate from epithelial cells. Epithelial cells and macrophages emerged as the strongest signal emitters and receivers, respectively. After reclustering epithelial cells and macrophages, our analysis, incorporating gene set variation analysis (GSVA), SCENIC analysis, and pseudotime trajectory analysis, indicated that subcluster 0 of epithelial cells (EP_0) showed a more malignant phenotype, and subclusters 3 and 4 of macrophages (M_3 and M_4) demonstrated heightened activity. Further analysis suggested that EP_0 may suppress the activity of M_3 and M_4 via MIF - (CD74 + CXCR4) in the MIF pathway. After analysing the expression of the 4 genes in the MIF pathway in both the TCGA cohort and our cohort (n = 61), CD74 was identified as significantly overexpressed in PTC tumours particularly those with lymph node metastasis. CONCLUSION: Our study revealed that PTC may facilitate lymph node metastasis by inhibiting macrophages via MIF signalling. It is suggested that malignant PTC cells may suppress the immune activity of macrophages by consistently releasing signals to them via MIF-(CD74 + CXCR4).


Assuntos
Fatores Inibidores da Migração de Macrófagos , Macrófagos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Feminino , Humanos , Oxirredutases Intramoleculares/metabolismo , Metástase Linfática/genética , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Macrófagos/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Análise da Expressão Gênica de Célula Única , Câncer Papilífero da Tireoide/imunologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia
7.
Cancer Immunol Res ; 12(1): 72-90, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37956411

RESUMO

Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes (TDE) contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSC) within the pancreatic cancer TME. However, the underlying mechanisms remain elusive. Herein, we report that macrophage migration inhibitory factor (MIF) in TDEs has a key role in inducing MDSC formation in pancreatic cancer. We identified MIF in both human and murine pancreatic cancer-derived exosomes. Upon specific shRNA-mediated knockdown of MIF, the ability of pancreatic cancer-derived exosomes to promote MDSC differentiation was abrogated. This phenotype was rescued by reexpression of the wild-type form of MIF rather than a tautomerase-null mutant or a thiol-protein oxidoreductase-null mutant, indicating that both MIF enzyme activity sites play a role in exosome-induced MDSC formation in pancreatic cancer. RNA sequencing data indicated that MIF tautomerase regulated the expression of genes required for MDSC differentiation, recruitment, and activation. We therefore developed a MIF tautomerase inhibitor, IPG1576. The inhibitor effectively inhibited exosome-induced MDSC differentiation in vitro and reduced tumor growth in an orthotopic pancreatic cancer model, which was associated with decreased numbers of MDSCs and increased infiltration of CD8+ T cells in the TME. Collectively, our findings highlight a pivotal role for MIF in exosome-induced MDSC differentiation in pancreatic cancer and underscore the potential of MIF tautomerase inhibitors to reverse the immunosuppressive pancreatic cancer microenvironment, thereby augmenting anticancer immune responses.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Células Supressoras Mieloides , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Diferenciação Celular , Linhagem Celular Tumoral , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Microambiente Tumoral
8.
J Investig Med ; 72(1): 17-25, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37803493

RESUMO

The most important complication of familial Mediterranean fever (FMF) is secondary amyloidosis. The aim of this study is to investigate the risk of developing FMF-related amyloidosis with macrophage migration inhibitory factor (MIF), interleukin 4 (IL-4), and IL-1 receptor antagonist (IL-1RA) variants. This study included 62 FMF patients with amyloidosis, 110 FMF patients without amyloidosis, and 120 controls. The clinical information of the patient groups was compared. MIF-173G/C, IL-4 variant number tandem repeat (VNTR), and IL-1RA VNTR variants were analyzed for all participants. The use of colchicine, pleurisy, and appendectomy was more common in FMF patients with amyloidosis than in FMF patients without amyloidosis. MIF-173G/C C/C genotype and C allele were higher in both patient groups compared to controls. IL-1RA VNTR A1/A2 and A1/A4 genotypes and A1-A4 alleles were more common in both patient groups than controls. The IL-4 VNTR P1 allele was more common in FMF patients with amyloidosis compared to controls. The MIF-173G/C allele and the IL-1RA VNTR A1-A4 allele are associated with FMF in the Turkish population but not with amyloidosis risk in FMF patients. The IL-4 VNTR P1 allele is more common in FMF patients with amyloidosis than in healthy individuals.


Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Fatores Inibidores da Migração de Macrófagos , Humanos , Amiloidose/genética , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-4/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Sequências de Repetição em Tandem
9.
Cell Death Dis ; 14(12): 795, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-38052787

RESUMO

Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Macrophage migration inhibitory factor (MIF) has long been recognized as a secreted cytokine in the pathogenesis of various human diseases, including cancer and autosomal dominant polycystic kidney disease (ADPKD). Unlike other cytokines, unique functional characteristics of intracellular MIF have emerged. In this study, we show that MIF is localized and formed a ring like structure at the proximal end of centrioles, where it regulates cilia biogenesis through affecting 1) the recruitment of TTBK2 to basal body and the removal of CP110 from mother centriole, 2) the accumulation of CEP290 at centriolar satellites, and 3) the trafficking of intraflagellar transport (IFT) related proteins. We also show that MIF functions as a novel transcriptional factor to regulate the expression of genes related to ciliogenesis via binding on the promotors of those genes. MIF also binds chromatin and regulates transcription of genes involved in diverse homeostatic signaling pathways. We identify phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) as an upstream regulator of MIF, which interacts with and phosphorylates MIF at S91 to increase its interaction with 14-3-3ζ, resulting in its nuclear translocation and transcription regulation. This study suggests that MIF is a key player in cilia biogenesis and a novel transcriptional regulator in homeostasis, which forward our understanding of how MIF is able to carry out several nonoverlapping functions.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Humanos , Fosforilação , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Cílios/metabolismo , Fosfatos/metabolismo , Proteínas 14-3-3/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo
10.
Sci Signal ; 16(812): eadg2621, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37988455

RESUMO

Mammalian macrophage migration inhibitory factor (MIF) and its paralog, D-dopachrome tautomerase, are multifunctional inflammatory cytokines. Plants have orthologous MIF and D-dopachrome tautomerase-like (MDL) proteins that mimic some of the effects of MIF on immune cells in vitro. We explored the structural and functional similarities between the three Arabidopsis thaliana MDLs and MIF. X-ray crystallography of the MDLs revealed high structural similarity between MDL and MIF homotrimers and suggested a potential explanation for the lack of tautomerase activity in the MDLs. MDL1 and MDL2 interacted with each other and with MIF in vitro, in yeast, and in plant leaves and formed hetero-oligomeric complexes with MIF in vitro. The MDLs stimulated signaling through the MIF receptors CXCR2 or CXCR4 and enhanced the responses to MIF in a yeast reporter system, in human neutrophils, and in human lung epithelial cells. Pharmacological inhibitors that disrupted MIF activity or prevented the formation of MIF-MDL hetero-oligomers blocked the observed synergism. These findings demonstrate that MDLs can enhance cellular responses to MIF, which may have functional implications in tissues exposed to MDLs from the diet or environment.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Animais , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/química , Proteínas de Plantas , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Saccharomyces cerevisiae/metabolismo , Neutrófilos/metabolismo , Mamíferos/metabolismo , Oxirredutases Intramoleculares/genética
11.
Biomed Pharmacother ; 168: 115673, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37857251

RESUMO

MIF/CD74 signaling pathway and autophagy may be closely related to liver fibrosis. Vanillic acid (VA) is likely to have an anti-liver fibrosis effect, although related studies have not been reported. The aim of this study was to verify the role of hepatic stellate cells (HSCs) autophagy and the MIF/CD74 signaling pathway in the pathogenesis of liver fibrosis, and to investigate the effect of VA on liver fibrosis through in vivo and in vitro experiments. Our results showed that VA significantly attenuated CCl4-induced liver fibrosis. The alleviation of liver fibrosis with VA treatment was associated with a reduction of MIF, CD74, α-SMA, LC3B and Collagen 1. In addition, VA, MIF inhibitor (ISO-1) and autophagy inhibitor (3-MA) markedly inhibited the proliferation and migration of HSCs. This study indicates that VA could protect against HSCs activation, proliferation and migration by inhibiting the autophagy in HSCs via the MIF/CD74 signaling pathway so that alleviates liver fibrosis.


Assuntos
Células Estreladas do Fígado , Fatores Inibidores da Migração de Macrófagos , Humanos , Células Estreladas do Fígado/metabolismo , Ácido Vanílico/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Transdução de Sinais , Autofagia , Fígado , Fatores Inibidores da Migração de Macrófagos/metabolismo , Oxirredutases Intramoleculares/metabolismo
12.
Mol Ther ; 31(11): 3117-3118, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37865098

RESUMO

The mechanistically defined attributes of primed MSCs as here described not only provide a novel use case of MIF activated MSCs that can address the potency shortcomings of generic culture-adapted MSCs for acute lung injury but also provide some intriguing "Rosetta Stone" insights on plausible in vivo physiology of MSCs with host innate effectors such as macrophages in response to inflammation.


Assuntos
Asma , Fatores Inibidores da Migração de Macrófagos , Transplante de Células-Tronco Mesenquimais , Animais , Camundongos , Humanos , Macrófagos , Asma/terapia , Inflamação , Transdução de Sinais , Calgranulina A , Fatores Inibidores da Migração de Macrófagos/genética , Oxirredutases Intramoleculares/genética
13.
Aging (Albany NY) ; 15(19): 10322-10346, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37796199

RESUMO

The deregulation of fatty acid metabolism plays a pivotal role in cancer. Our objective is to construct a prognostic model for patients with endometrial carcinoma (EC) based on genes related to fatty acid metabolism-related genes (FAMGs). RNA sequencing and clinical data for EC were obtained from The Cancer Genome Atlas (TCGA). Lasso-Penalized Cox regression was employed to derive the risk formula for the model, the score = esum(corresponding coefficient × each gene's expression). Gene set enrichment analysis (GSEA) was utilized to examine the enrichment of KEGG and GO pathways within this model. Correlation analysis of immune function was conducted using Single-sample GSEA (ssGSEA). The "ESTIMATE" package in R was utilized to evaluate the tumor microenvironment. The support vector machine recursive feature elimination (SVM-RFE) and randomforest maps were employed to identify key genes. The effects of PTGIS on the malignant biological behavior of EC were assessed through CCK-8 assay, transwell invasion assay, cell cycle analysis, apoptosis assay, and tumor xenografts in nude mice. A novel prognostic signature comprising 10 FAMGs (INMT, ACACB, ACOT4, ACOXL, CYP4F3, FAAH, GPX1, HPGDS, PON3, PTGIS) was developed. This risk score serves as an independent prognostic marker validated for EC. According to ssGSEA analysis, the low- and high-risk groups exhibited distinct immune enrichments. The key gene PTGIS was screened by SVM-RFE and randomforest method. Furthermore, we validated the expression of PTGIS through qRT-PCR. In vitro and in vivo experiments also confirmed the effect of PTGIS on the malignant biological behavior of EC.


Assuntos
Neoplasias do Endométrio , Animais , Camundongos , Feminino , Humanos , Camundongos Nus , Neoplasias do Endométrio/genética , Oxirredutases Intramoleculares , Ácidos Graxos , Microambiente Tumoral , Sistema Enzimático do Citocromo P-450
14.
Exp Eye Res ; 236: 109669, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37774962

RESUMO

Therapeutic management of inflammation in infectious keratitis (IK) requires new strategy and targets for selective immunomodulation. Targeting host cell-type specific inflammatory responses might be a viable strategy to curtail unnecessary inflammation and reduce tissue damage without affecting pathogen clearance. This study explores the possibility of pathogen and host cell-type dependent differences in the inflammatory pathways relevant in the pathogenesis of IK. Human corneal epithelial cell line (HCEC) and phorbol 12-myristate-13 acetate (PMA) differentiated THP-1 macrophage line were infected with either Aspergillus flavus conidia or Acanthamoeba castellanii trophozoites and the elicited inflammatory responses were studied in terms of gene expression and secretion of proinflammatory factors interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) and an upstream inflammatory regulator and mediator protein-the Macrophage Migration Inhibitory Factor (MIF). Given the pleotropic mode of MIF function in diverse cell types relevant in many human diseases, we tested if MIF driven responses to infection is different in HCECs and THP-1 macrophages by studying its expression, secretion and involvement in inflammation by siRNA mediated knockdown. We also examined IK patient tear samples for MIF levels. Infection with A. flavus or A. castellanii induced IL-8 and TNF-α responses in HCECs and THP-1 macrophages but to different levels. Our preliminary human data showed that the level of secreted MIF protein was elevated in IK patient tear, however, MIF secretion by the two cell types were strikingly different in-vitro, under both normal and infected conditions. We found that HCECs released MIF constitutively, which was significantly inhibited with infection, whereas THP-1 macrophages were stimulated to release MIF during infection. MIF gene expression remained largely unaffected by infection in both the cell lines. Although MIF in HCECs appeared to be intracellularly captured during infection, MIF knockdown in HCECs associated with a partial reduction of the IL-8 and TNF-α expression produced by either of the pathogens, suggesting a pro-inflammatory role for MIF in HCECs, independent of its canonical cytokine like function. In contrast, MIF knockdown in THP-1 macrophages accompanied a dramatic increase in IL-8 and TNF-α expression during A. castellanii infection, while the responses to A. flavus infection remained unchanged. These data imply a host cell-type and pathogen specific distinction in the MIF- related inflammatory signaling and MIF as a potential selective immunomodulatory target in infectious keratitis.


Assuntos
Ceratite , Fatores Inibidores da Migração de Macrófagos , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Fator de Necrose Tumoral alfa , Interleucina-8/genética , Inflamação , Imunomodulação , Oxirredutases Intramoleculares
15.
FASEB J ; 37(10): e23202, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37732633

RESUMO

Trichinellosis caused by Trichinella spiralis (T. spiralis) is a major food-borne parasitic zoonosis worldwide. Prevention of trichinellosis is an effective strategy to improve patient quality of life. Macrophage migration inhibitory factor (MIF) is closely related to the occurrence and development of several parasitic diseases. Studying the impact of MIF deficiency (Mif-/- ) on the alterations in host fecal microbiota due to T. spiralis infection may contribute to proposing a novel dual therapeutic approach for trichinellosis. To reveal the diversity and differences in fecal microbial composition, feces were collected from T. spiralis-uninfected and T. spiralis-infected wild-type (WT) and MIF knockout (KO) C57BL/6 mice at 0, 7, 14, and 35 days post-infection (dpi), and the samples were sent for 16S rRNA amplicon sequencing on the Illumina NovaSeq platform. Flow cytometry was used to determine the expression levels of IFN-γ and IL-4 in the CD4+ /CD8+ T-cell sets of mouse spleens. The results showed that operational taxonomic unit (OTU) clustering, relative abundance of microbial composition, alpha diversity, and beta diversity exhibited significant changes among the eight groups. The LEfSe analysis selected several potential biomarkers at the genus or species level, including Akkermansia muciniphila, Lactobacillus murinus, Coprococcus catus, Firmicutes bacterium M10_2, Parabacteroides sp. CT06, and Bacteroides between the KTs and WTs groups. The predicted bacterial functions of the fecal microbiota were mainly involved in metabolism, such as the metabolism of carbohydrates, amino acids, energy, cofactors, vitamins, nucleotides, glycans, and lipids. Flow cytometry revealed an increased CD3+ CD8- /CD3+ CD8+ T-cell ratio and increased IFN-γ and IL-4 levels in CD3+ CD8- T-cell sets from WT and MIF KO mice at 7 dpi. The results indicated that both MIF KO and infection time have a significant influence on the CD3+ CD8- IFN-γ+ and CD3+ CD8- IL-4+ response in mice after T. spiralis. In conclusion, this research showed alterations of the fecal microbiota and immune response in both WT and MIF KO mice before and after T. spiralis infection. These results revealed a potential role of MIF in regulating the pathogenesis of trichinellosis related to the intestinal microbiota. Importantly, the selected potential biomarkers combined with MIF will also offer a novel therapeutic approach to treat trichinellosis in the future.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Microbiota , Trichinella spiralis , Triquinelose , Animais , Humanos , Camundongos , Interleucina-4 , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos Endogâmicos C57BL , Qualidade de Vida , RNA Ribossômico 16S/genética
16.
PeerJ ; 11: e15933, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37645013

RESUMO

Objective: This study aimed to investigate the correlation between serum levels of macrophage migration inhibitory factor (MIF) and the condition and prognosis of patients with traumatic brain injury (TBI). Methods: A retrospective study design was used, and the clinical data of 131 TBI patients from February 2019 to January 2022 were analyzed. Patients were divided into mild (13-15 points), moderate (9-12 points), or severe (3-8 points) groups according to their Glasgow Coma Scale (GCS) score after admission. The serum levels of BDNF, MIF, and MBP in the three groups were compared, and their correlation with the severity of TBI was analyzed. Patients were then separated into a good prognosis group (4-5 points) and a poor prognosis group (≤3 points) based on their Glasgow Prognostic Score (GOS) after 6 months of follow-up. The predictive power of serum indexes and combined detection on prognosis was analyzed. Results: Patients were classified into a mild group (n = 63), moderate group (n = 47), and severe group (n = 21) based on their GCS, with a significant difference noted in serum levels of MIF, MBP, and BDNF among patients with different degrees of severity (all P < 0.001). The MIF, MBP, and BDNF levels were lower in the mild group compared to the moderate (all P < 0.001) and severe group (all P < 0.001). Additionally, the MIF and BDNF levels in the moderate group were lower compared to the severe group (P = 0.011, P = 0.002). Patients with mild severity had lower serum MIF, MBP, and BDNF levels than those with other degrees, and these indexes were positively correlated with the severity of TBI (all P < 0.001, r = 0.62, r = 0.48, r = 0.58). Based on the GOS, patients were divided into a good prognosis group (n = 107) and a poor prognosis group (n = 24), with the levels of MIF, MBP, and BDNF in the good prognosis group being significantly lower than those in the poor prognosis group (P < 0.001, P = 0.007, P = 0.003). The area under the curve (AUC) of MIF was higher than that of MBP and BDNF in predicting the prognosis of TBI patients; however, the statistical differences were not significant (MIF vs. MBP, P = 0.239; MIF vs. BDNF, P = 0.211; BDNF vs. MBP, P = 0.899). The center line has a large displacement, CT annular cisterna compression, increased white blood cell count, MBP and BDNF were risk factors for prognosis in TBI patients (P = 0.005, P = 0.001, P = 0.005, P = 0.033, P = 0.044). Conclusion: The serum levels of MIF, MBP, and BDNF in TBI patients were positively correlated with the severity of the disease, and MBP, BDNF levels had predictive value in determining patient prognosis.


Assuntos
Lesões Encefálicas Traumáticas , Traumatismos Craniocerebrais , Fatores Inibidores da Migração de Macrófagos , Humanos , Estudos Retrospectivos , Fator Neurotrófico Derivado do Encéfalo , Lesões Encefálicas Traumáticas/diagnóstico , Prognóstico , Oxirredutases Intramoleculares
17.
Cancer Res Commun ; 3(7): 1397-1408, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37529399

RESUMO

The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited similar tumorigenicity to that of COX-2-deficient cells, despite a lower ability to suppress PGE2 synthesis by mPGES-1 depletion, indicating the presence of factors other than PGE2 that are likely to regulate tumor immunity. RNA-sequencing analysis revealed that mPGES-1 depletion reduced the expressions of collagen-related genes, which have been found to be associated with immunosuppressive signatures. In our mouse model, collagen was reduced in mPGES-1-deficient tumors, and phenotypic analysis of tumor-infiltrating lymphocytes indicated that mPGES-1-deficient tumors had fewer TIM3+ exhausted CD8+ T cells compared with COX-2-deficient tumors. CAY10678, an mPGES-1 inhibitor, was equivalent to celecoxib, a selective COX-2 inhibitor, in reinforcing anti-PD-1 treatment. Our study indicates that mPGES-1 inhibitors represent a promising adjuvant for immunotherapies in melanoma by reducing collagen deposition and T-cell exhaustion. Significance: Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression. We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.


Assuntos
Oxirredutases Intramoleculares , Melanoma , Animais , Camundongos , Prostaglandina-E Sintases/genética , Oxirredutases Intramoleculares/genética , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Exaustão das Células T , Melanoma/tratamento farmacológico , Ciclo-Oxigenase 1 , Colágeno , Imunoterapia , Microambiente Tumoral
18.
Plant Physiol ; 193(2): 1621-1634, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37392433

RESUMO

Allene oxide cyclase (AOC) is a key enzyme in the biosynthesis of jasmonic acid (JA), which is involved in plant growth and development as well as adaptation to environmental stresses. We identified the cold- and pathogen-responsive AOC2 gene from Medicago sativa subsp. falcata (MfAOC2) and its homolog MtAOC2 from Medicago truncatula. Heterologous expression of MfAOC2 in M. truncatula enhanced cold tolerance and resistance to the fungal pathogen Rhizoctonia solani, with greater accumulation of JA and higher transcript levels of JA downstream genes than in wild-type plants. In contrast, mutation of MtAOC2 reduced cold tolerance and pathogen resistance, with less accumulation of JA and lower transcript levels of JA downstream genes in the aoc2 mutant than in wild-type plants. The aoc2 phenotype and low levels of cold-responsive C-repeat-binding factor (CBF) transcripts could be rescued by expressing MfAOC2 in aoc2 plants or exogenous application of methyl jasmonate. Compared with wild-type plants, higher levels of CBF transcripts were observed in lines expressing MfAOC2 but lower levels of CBF transcripts were observed in the aoc2 mutant under cold conditions; superoxide dismutase, catalase, and ascorbate-peroxidase activities as well as proline concentrations were higher in MfAOC2-expressing lines but lower in the aoc2 mutant. These results suggest that expression of MfAOC2 or MtAOC2 promotes biosynthesis of JA, which positively regulates expression of CBF genes and antioxidant defense under cold conditions and expression of JA downstream genes after pathogen infection, leading to greater cold tolerance and pathogen resistance.


Assuntos
Ciclopentanos , Oxilipinas , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fenótipo , Regulação da Expressão Gênica de Plantas
19.
Mol Genet Genomic Med ; 11(11): e2252, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37485818

RESUMO

BACKGROUND: Some cytokines are strongly implicated in the development of squamous cell carcinoma (SCC) such as the Macrophage migration inhibitory factor (MIF). The haplotype -794 (CATT)5-8 /-173G>C in MIF gene polymorphisms has been associated with some types of cancer. The aim of this study is to establish the possible association between the presence of this haplotype in the MIF gene and its subsequent soluble levels with the susceptibility of SCC in western Mexican population. METHODS: This study included 175 SCC patients and 175 age-sex-matched individuals as a reference group (RG) from western Mexico. Genomic DNA was extracted from peripheral blood leukocytes. Polymorphisms were genotyped by endpoint PCR and PCR-RFLP, and the determination of MIF serum levels was measured by ELISA. Clinical characteristics were evaluated by a group of dermatologists. RESULTS: Analysis of [-794(CATT)5-8 /-173G>C] MIF gene polymorphisms showed that the 5C (OR = 2.7, p = 0.02) and the 7G (OR = 3.39, p < 0.01) haplotypes are associated with susceptibility in SCC. MIF soluble levels in SCC patients showed a median of 13.93 ng/mL, whereas the reference group showed 6.000 ng/mL. CONCLUSIONS: Our findings suggest that 5C and 7G [-794(CATT)5-8 /-173G>C] MIF gene haplotypes are associated with susceptibility to SCC and that SCC patients present increased soluble levels of MIF.


Assuntos
Carcinoma de Células Escamosas , Fatores Inibidores da Migração de Macrófagos , Neoplasias Cutâneas , Humanos , Haplótipos , Carcinoma de Células Escamosas/genética , México , Predisposição Genética para Doença , Neoplasias Cutâneas/genética , Polimorfismo Genético , Fatores Inibidores da Migração de Macrófagos/genética , Oxirredutases Intramoleculares/genética
20.
FASEB J ; 37(8): e23072, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37498233

RESUMO

Macrophage migration inhibitory factor (MIF) expression is controlled by a functional promoter polymorphism, where the number of tetranucleotide repeats (CATTn ) corresponds to the level of MIF expression. To examine the role of this polymorphism in a pre-clinical model of allergic asthma, novel humanized MIF mice with increasing CATT repeats (CATT5 and CATT7 ) were used to generate a physiologically relevant scale of airway inflammation following house dust mite (HDM) challenge. CATT7 mice expressing high levels of human MIF developed an aggressive asthma phenotype following HDM challenge with significantly elevated levels of immune cell infiltration, production of inflammatory mediators, goblet cell hyperplasia, subepithelial collagen deposition, and airway resistance compared to wild-type controls. Importantly the potent MIF inhibitor SCD-19 significantly mitigated the pathophysiology observed in CATT7 mice after HDM challenge, demonstrating the fundamental role of endogenous human MIF expression in the severity of airway inflammation in vivo. Up to now, there are limited reproducible in vivo models of asthma airway remodeling. Current asthma medications are focused on reducing the acute inflammatory response but have limited effects on airway remodeling. Here, we present a reproducible pre-clinical model that capitulates asthma airway remodeling and suggests that in addition to having pro-inflammatory effects MIF may play a role in driving airway remodeling.


Assuntos
Asma , Fatores Inibidores da Migração de Macrófagos , Humanos , Animais , Camundongos , Pyroglyphidae , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Remodelação das Vias Aéreas , Pulmão/metabolismo , Inflamação/metabolismo , Modelos Animais de Doenças , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo
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