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Zahoor I, Pan G, Cerghet M, Elbayoumi T, Mao-Draayer Y, Giri S, Palaniyandi SS. Current understanding of cardiovascular autonomic dysfunction in multiple sclerosis. Heliyon 2024; 10:e35753. [PMID: 39170118 PMCID: PMC11337049 DOI: 10.1016/j.heliyon.2024.e35753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Autoimmune diseases, including multiple sclerosis (MS), are proven to increase the likelihood of developing cardiovascular disease (CVD) due to a robust systemic immune response and inflammation. MS can lead to cardiovascular abnormalities that are related to autonomic nervous system dysfunction by causing inflammatory lesions surrounding tracts of the autonomic nervous system in the brain and spinal cord. CVD in MS patients can affect an already damaged brain, thus worsening the disease course by causing brain atrophy and white matter disease. Currently, the true prevalence of cardiovascular dysfunction and associated death rates in patients with MS are mostly unknown and inconsistent. Treating vascular risk factors is recommended to improve the management of this disease. This review provides an updated summary of CVD prevalence in patients with MS, emphasizing the need for more preclinical studies using animal models to understand the pathogenesis of MS better. However, no distinct studies exist that explore the temporal effects and etiopathogenesis of immune/inflammatory cells on cardiac damage and dysfunction associated with MS, particularly in the cardiac myocardium. To this end, a thorough investigation into the clinical presentation and underlying mechanisms of CVD must be conducted in patients with MS and preclinical animal models. Additionally, clinicians should monitor for cardiovascular complications while prescribing medications to MS patients, as some MS drugs cause severe CVD.
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Affiliation(s)
- Insha Zahoor
- Department of Neurology, Henry Ford Health, Detroit, MI, USA
| | - Guodong Pan
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health, Detroit, MI, USA
| | - Mirela Cerghet
- Department of Neurology, Henry Ford Health, Detroit, MI, USA
| | - Tamer Elbayoumi
- Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ, USA
| | - Yang Mao-Draayer
- Multiple Sclerosis Center of Excellence, Autoimmunity Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Shailendra Giri
- Department of Neurology, Henry Ford Health, Detroit, MI, USA
| | - Suresh Selvaraj Palaniyandi
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health, Detroit, MI, USA
- Department of Physiology, Wayne State University, Detroit, MI, USA
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Dong Z, Yang P, Ji Z, Fan C, Wang J, Zhu P, Zhou F, Gan M, Wu X, Geng D. MIF inhibition attenuates intervertebral disc degeneration by reducing nucleus pulposus cell apoptosis and inflammation. Exp Cell Res 2024; 439:114089. [PMID: 38740166 DOI: 10.1016/j.yexcr.2024.114089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 05/01/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Nucleus pulposus cells (NPCs) apoptosis and inflammation are the extremely critical factors of intervertebral disc degeneration (IVDD). Nevertheless, the underlying procedure remains mysterious. Macrophage migration inhibitory factor (MIF) is a cytokine that promotes inflammation and has been demonstrated to have a significant impact on apoptosis and inflammation. For this research, we employed a model of NPCs degeneration stimulated by lipopolysaccharides (LPS) and a rat acupuncture IVDD model to examine the role of MIF in vitro and in vivo, respectively. Initially, we verified that there was a significant rise of MIF expression in the NP tissues of individuals with IVDD, as well as in rat models of IVDD. Furthermore, this augmented expression of MIF was similarly evident in degenerated NPCs. Afterwards, it was discovered that ISO-1, a MIF inhibitor, effectively decreased the quantity of cells undergoing apoptosis and inhibited the release of inflammatory molecules (TNF-α, IL-1β, IL-6). Furthermore, it has been shown that the PI3K/Akt pathway plays a vital part in the regulation of NPCs degeneration by MIF. Ultimately, we showcased that the IVDD process was impacted by the MIF inhibitor in the rat model. In summary, our experimental results substantiate the significant involvement of MIF in the degeneration of NPCs, and inhibiting MIF activity can effectively mitigate IVDD.
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Affiliation(s)
- Zhongchen Dong
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China; Wujin Hospital Affiliated Hospital, Jiangsu University, Changzhou, Jiangsu, China
| | - Peng Yang
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Zhongwei Ji
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China; Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Chunyang Fan
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Jiale Wang
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Pengfei Zhu
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Feng Zhou
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Minfeng Gan
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Xiexing Wu
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Dechun Geng
- Orthopaedic Institute, Department of Orthopaedic Surgery, the First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
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Zerpa-Hernández DA, García-Chagollán M, Sánchez-Zuno GA, García-Arellano S, Hernández-Bello J, Hernández-Palma LA, Cerpa-Cruz S, Martinez-Bonilla G, Nicoletti F, Muñoz-Valle JF. Expression of Transcriptional Factors of T Helper Differentiation (T-bet, GATA-3, RORγt, and FOXP3), MIF Receptors (CD44, CD74, CXCR2, 4, 7), and Th1, Th2, and Th17 Cytokines in PBMC from Control Subjects and Rheumatoid Arthritis Patients. Curr Mol Med 2024; 24:1169-1182. [PMID: 37807647 DOI: 10.2174/0115665240260976230925095330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 08/09/2023] [Accepted: 08/11/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION The macrophage migration inhibitory factor (MIF) plays a pivotal role in the development of rheumatoid arthritis (RA). Previous research indicates that MIF can trigger the expression of cytokine profiles associated with Th1, Th2, and Th17 responses in peripheral blood mononuclear cells (PBMC) from both RA patients and control subjects (CS). Despite these, few studies to date precisely elucidate the molecular mechanisms involved. The present study aimed to associate the expression of Th differentiation TF (T-bet, GATA-3, RORγt) with MIF receptors (CD44, CD74, CXCR2, 4, 7) and Th1, Th2, and Th17 cytokines in PBMC from CS and RA patients. METHOD PBMC from both groups was cultured for 24 h. The expression of the canonical and non-canonical MIF receptors and the TF was determined by flow cytometry. Additionally, multiplex bead analysis was employed to assess the levels of cytokines in the culture supernatants. The findings revealed that T CD4+ lymphocytes in the CS group exhibited a heightened expression of CD74 (p<0.05), whereas RA patients displayed an elevated expression of CXCR7 (p<0.001). Furthermore, T CD4+ lymphocytes from RA patients exhibited greater expression of GATA3, RORγt, and FOXP3, along with elevated levels of pro-inflammatory cytokines compared to the CS group (p<0.001). RESULT These results indicate that CD74 is more prominently expressed in PBMC from the CS group, whereas CXCR7 is more expressed in PBMC from RA patients. CONCLUSION We also noted an increased secretion of Th17 profile cytokines in RA, potentially influenced by the activation of FOXP3 via CD74 and RORγt through CXCR7 using the endocytic pathway.
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Affiliation(s)
| | - Mariel García-Chagollán
- Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Jalisco 44340, México
| | | | - Samuel García-Arellano
- Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Jalisco 44340, México
| | - Jorge Hernández-Bello
- Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Jalisco 44340, México
| | - Luis Alexis Hernández-Palma
- Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Jalisco 44340, México
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Universidad de Guadalajara, Jalisco 49000, Mexico
| | - Sergio Cerpa-Cruz
- Servicio de Reumatología, O.P.D. Hospital Civil de Guadalajara "Fray Antonio Alcalde", Jalisco 44280, Mexico
| | - Gloria Martinez-Bonilla
- Servicio de Reumatología, O.P.D. Hospital Civil de Guadalajara "Fray Antonio Alcalde", Jalisco 44280, Mexico
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
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Kaanane H, Senhaji N, Berradi H, Benchakroun N, Benider A, Karkouri M, El Attar H, Flores O, Khyatti M, Nadifi S. The influence of Interleukin-6, Interleukin-8, Interleukin-10, Interleukin-17, TNF-A, MIF, STAT3 on lung cancer risk in Moroccan population. Cytokine 2022; 151:155806. [PMID: 35065510 DOI: 10.1016/j.cyto.2022.155806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 12/04/2021] [Accepted: 01/09/2022] [Indexed: 12/28/2022]
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Parol-Kulczyk M, Gzil A, Maciejewska J, Bodnar M, Grzanka D. Clinicopathological significance of the EMT-related proteins and their interrelationships in prostate cancer. An immunohistochemical study. PLoS One 2021; 16:e0253112. [PMID: 34157052 PMCID: PMC8219170 DOI: 10.1371/journal.pone.0253112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 05/29/2021] [Indexed: 11/19/2022] Open
Abstract
The chronic inflammation influences a microenvironment, where as a result of losing control over tissue homeostatic mechanisms, the carcinogenesis process may be induced. Inflammatory response cells can secrete a number of factors that support both initiation and progression of cancer and also they may consequently induct an epithelial-mesenchymal transition (EMT), the process responsible for development of distant metastasis. Macrophage migration inhibitory factor (MIF) acts as a pro-inflammatory cytokine that is considered as a link between chronic inflammation and tumor development. MIF can function as a modulator of important cancer-related genes expression, as well as an activator of signaling pathways that promotes the development of prostate cancer. The study was performed on FFPE tissues resected from patients who underwent radical prostatectomy. To investigate the relationship of studied proteins with involvement in tumor progression and initiation of epithelial-to-mesenchymal transition (EMT) process, we selected clinicopathological parameters related to tumor progression. Immunohistochemical analyses of MIF, SOX-4, β-catenin and E-cadherin were performed on TMA slides. We found a statistically significant correlation of overall β-catenin expression with the both lymph node metastasis (p<0.001) and presence of angioinvasion (p = 0.012). Membrane β-catenin expression was associated with distant metastasis (p = 0.021). In turn, nuclear MIF was correlated with lymph node metastasis (p = 0.003). The positive protein-protein correlations have been shown between the total β-catenin protein expression level with level of nuclear SOX-4 protein expression (r = 0.27; p<0.05) as well as negative correlation of β-catenin expression with level of nuclear MIF protein expression (r = -0.23; p<0.05). Our results seem promising and strongly highlight the potential role of MIF in development of nodal metastases as well as may confirm an involvement of β-catenin in disease spread in case of prostate cancer.
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Affiliation(s)
- Martyna Parol-Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Joanna Maciejewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Magdalena Bodnar
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
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Pleural cytokines MIF and MIP-3α as novel biomarkers for complicated parapneumonic effusions and empyema. Sci Rep 2021; 11:1763. [PMID: 33469074 PMCID: PMC7815762 DOI: 10.1038/s41598-021-81053-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 12/02/2020] [Indexed: 11/20/2022] Open
Abstract
Patients with complicated parapneumonic effusion (CPPE)/empyema have high morbidity and mortality, particularly when adequate management is delayed. We aimed to investigate novel dysregulated cytokines that can be used as biomarkers for infectious pleural effusions, especially for CPPE/empyema. Expression of 40 cytokines in parapneumonic effusions (PPE) was screened in the discovery phase, involving 63 patients, using a multiplex immunobead-based assay. Six cytokines were subsequently validated by enzyme-linked immunosorbent assays (ELISAs). We then used ELISA to further evaluate the diagnostic values and cutoff values of these cytokines as potential biomarkers in an expanded group that included 200 patients with uncomplicated parapneumonic effusion (UPPE), CPPE, empyema, transudates, other exudates, and malignant pleural effusion (MPE). The pleural levels of four cytokines (MIF, MIP-3α, IL-1β, ENA-78) were highest and significantly increased in CPPE/empyema compared with those in other etiologies. According to receiver operating characteristic curve analysis, the four cytokines (MIF, MIP-3α, IL-1β, and ENA-78) had areas under the curve (AUCs) greater than 0.710 for discriminating parapneumonic pleural effusion from noninfectious pleural effusions. In a comparison of nonpurulent CPPE with UPPE, logistic regression analysis revealed that pleural fluid MIF ≥ 12 ng/ml and MIP-3α ≥ 4.3 ng/ml had the best diagnostic value; MIF also displayed the highest odds ratio of 663 for nonpurulent CPPE, with 97.5% specificity, 94.44% sensitivity, and an AUC of 0.950. In conclusion, our results show that elevated MIF and MIP-3α may be used as novel biomarkers for PPE diagnosis, particularly in patients with CPPE/empyema; the findings indicate that dysregulated cytokine expression may provide clues about the pathogenesis of pleural infection.
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Juárez-Avelar I, Rodríguez T, García-García AP, Rodríguez-Sosa M. Macrophage migration inhibitory factor (MIF): Its role in the genesis and progression of colorectal cancer. IMMUNOTHERAPY IN RESISTANT CANCER: FROM THE LAB BENCH WORK TO ITS CLINICAL PERSPECTIVES 2021:173-193. [DOI: 10.1016/b978-0-12-822028-3.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Structural and functional insights into macrophage migration inhibitory factor from Oncomelania hupensis, the intermediate host of Schistosoma japonicum. Biochem J 2020; 477:2133-2151. [PMID: 32484230 DOI: 10.1042/bcj20200068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 11/17/2022]
Abstract
Oncomelania hupensis is the unique intermediate host of Schistosoma japonicum. As an irreplaceable prerequisite in the transmission and prevalence of schistosomiasis japonica, an in-depth study of this obligate host-parasite interaction can provide glimpse into the molecular events in the competition between schistosome infectivity and snail immune resistance. In previous studies, we identified a macrophage migration inhibitory factor (MIF) from O. hupensis (OhMIF), and showed that it was involved in the snail host immune response to the parasite S. japonicum. Here, we determined the crystal structure of OhMIF and revealed that there were distinct structural differences between the mammalian and O. hupensis MIFs. Noticeably, there was a projecting and structured C-terminus in OhMIF, which not only regulated the MIF's thermostability but was also critical in the activation of its tautomerase activity. Comparative studies between OhMIF and human MIF (hMIF) by analyzing the tautomerase activity, oxidoreductase activity, thermostability, interaction with the receptor CD74 and activation of the ERK signaling pathway demonstrated the functional differences between hMIF and OhMIF. Our data shed a species-specific light on structural, functional, and immunological characteristics of OhMIF and enrich the knowledge on the MIF family.
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Shomali N, Mahmoudi J, Mahmoodpoor A, Zamiri RE, Akbari M, Xu H, Shotorbani SS. Harmful effects of high amounts of glucose on the immune system: An updated review. Biotechnol Appl Biochem 2020; 68:404-410. [PMID: 32395846 DOI: 10.1002/bab.1938] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022]
Abstract
Release and storage of energy can be regulated by the metabolic parameter dependent on the central nervous system. Macrophages are one of the most professional antigen-presenting cells that are formed by the accumulation of dead or damaged cells or in response to the infection, which has the main function of phagocytosis, secretion of cytokines, and presenting antigen to T cells. A proper immune response is needed for the production of effector cytokines along with comprehensive and rapid cell proliferation and growth. Activation of the immune system and immune cells is needed to increase glucose metabolism. When the immune system responds to pathogens, chemokines inform immune cells such as macrophages and T cells to travel to the infected area. Although glucose is vital for the proper function of immune cells and their proliferation, a high amount of glucose may lead to impaired function of the immune system and pathological conditions. However, a suitable amount of glucose is indispensable for the immune system, but its elevated amount leads to excessive proinflammatory cytokines production. In this study, we focused on the master regulatory role of glucose on the immune system.
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Affiliation(s)
- Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology and Critical Care Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Eghdam Zamiri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Huaxi Xu
- Department of Immunology, Jiangsu University, Zhenjiang, People's Republic of China
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Jiangsu University, Zhenjiang, People's Republic of China
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Wen L, Liu L, Shen X, Li H, Zhu Z, Huang H, Cai M, Qian D, Shen S, Qiu Y, Cui Y, Sheng Y. The association of the UHRF1BP1 gene with systemic lupus erythematosus was replicated in a Han Chinese population from mainland China. Ann Hum Genet 2020; 84:221-228. [PMID: 31691269 DOI: 10.1111/ahg.12362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 08/15/2019] [Accepted: 10/04/2019] [Indexed: 12/14/2022]
Abstract
Single-nucleotide polymorphisms (SNPs) in the UHRF gene have been shown to be associated with systemic lupus erythematosus (SLE) in European and Hong Kong Chinese, but statistically significant evidence for association has not been found in a mainland Han Chinese population. Therefore, we selected SNP rs13205210 located in UHRF1BP1 as a candidate association from our previously published genome-wide association study (GWAS) data of SLE (1,047 cases and 1,205 controls from a mainland Han Chinese population) to explore the association between the UHRF1BP1 gene and SLE. We conducted a large-scale replication study in an additional independent sample of 3,509 cases and 8,246 controls from a mainland Han Chinese population. Real-time PCR was used to determine gene expression differences in peripheral blood mononuclear cells (PBMCs) from cases and controls. As a result, we replicated the association between the UHRF1BP1 gene and SLE (rs13205210, missense, Pmeta = 2.26E-17, odds ratio = 1.41) by a meta-analysis of our previous GWAS and this replication study involving a total of 4,556 cases and 9,451 controls. The UHRF1BP1 mRNA expression level in PBMCs was significantly decreased in patients with SLE compared with that in healthy controls. SNP rs13205210 exhibited an expression quantitative trait loci effect on the UHRF1BP1 gene in PBMCs from patients. In conclusion, this study not only suggests that the UHRF1BP1 gene was associated with SLE in a mainland Han Chinese population, but also implied that it might be a common genetic factor contributing to SLE susceptibility in multiple populations.
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Affiliation(s)
- Leilei Wen
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Lu Liu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Xue Shen
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Hui Li
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Zhengwei Zhu
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - He Huang
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Minglong Cai
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Danfeng Qian
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Songke Shen
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
| | - Ying Qiu
- Department of Dermatology, Jining No. 1 People's Hospital, Shandong, China
| | - Yong Cui
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Department of Dermatology, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Yujun Sheng
- Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China
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Le M, Muntyanu A, Netchiporouk E. IncRNAs and circRNAs provide insight into discoid lupus pathogenesis and progression. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:260. [PMID: 32355704 PMCID: PMC7186711 DOI: 10.21037/atm.2020.03.56] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Michelle Le
- Division of Dermatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Anastasiya Muntyanu
- Division of Dermatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Elena Netchiporouk
- Division of Dermatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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Chen CA, Chang JM, Yang YL, Chang EE, Chen HC. Macrophage migration inhibitory factor regulates integrin-β1 and cyclin D1 expression via ERK pathway in podocytes. Biomed Pharmacother 2020; 124:109892. [PMID: 31986415 DOI: 10.1016/j.biopha.2020.109892] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/02/2020] [Accepted: 01/10/2020] [Indexed: 11/29/2022] Open
Abstract
AIMS Macrophage migration inhibitory factor (MIF) is found to increase in proliferative glomerulonephritis. MIF binds to the MIF receptor (CD74) that activates MAP kinase (ERK and p38). Integrins and cyclinD1 regulate cell proliferation, differentiation and adhesion. This study evaluates whether MIF can regulate integrin-β1/cyclin D1 expression and cell adhesion of podocytes. MAIN METHODS Expression of integrin-β1 mRNA/protein and cyclin D1 mRNA under stimulation of MIF was evaluated by real-time PCR and Western blotting. MIF receptor (CD74) and MAP kinase under MIF treatment were examined to determine which pathway regulated integrin-β1 and cyclin D1 expression. Cell adhesion was evaluated under MIF treatment and/or anti-integrin-β1 antibody by cell adhesion assay. KEY FINDINGS Protein levels of integrin-β1 were up-regulated under MIF treatment in a dosage-dependent manner. CD74 protein levels were not changed after MIF treatment. Integrin-β1 and cyclin D1 mRNA levels were up-regulated after MIF 100 ng/ml treatment. ERK inhibitor U0126 reduced MIF-induced the increase in integrin-β1 mRNA and protein expression following MIF stimulation. However, p38 inhibitor SB 203580 did not inhibit MIF-induced increase in integrin-β1 mRNA and protein expression following MIF stimulation. MIF-induced increase in cyclin D1 mRNA level also was inhibited only by U0126 following MIF stimulation. Podocyte adhesion was increased after MIF treatment, but, anti-integrin-β1 antibody decreased MIF-enhanced podocyte adhesion. SIGNIFICANCE MIF increases integrin-β1 and cyclin D1 expression through the ERK pathway in podocytes, and the up-regulated expression of integrin-β1 increases podocyte adhesion. These results provide further understanding for the role of MIF in developing proliferative glomerulonephritis.
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Affiliation(s)
- Chien-An Chen
- Department of Nephrology, Tainan Sinlau Hospital, Tainan, 701, Taiwan; Department of Health Care Administration, Chang Jung Christian University, Tainan, 711, Taiwan.
| | - Jer-Ming Chang
- Department of Nephrology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Yu-Lin Yang
- Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, 703, Taiwan
| | - Eddy-Essen Chang
- Department of Nephrology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Hung-Chun Chen
- Department of Nephrology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
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13
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Cuzzoni E, Franca R, De Iudicibus S, Marcuzzi A, Lucafò M, Pelin M, Favretto D, Monti E, Morello W, Ghio L, La Scola C, Mencarelli F, Pasini A, Montini G, Decorti G, Stocco G. MIF plasma level as a possible tool to predict steroid responsiveness in children with idiopathic nephrotic syndrome. Eur J Clin Pharmacol 2019; 75:1675-1683. [PMID: 31463578 DOI: 10.1007/s00228-019-02749-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 08/13/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. METHODS The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. RESULTS Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-3-6.7 × 10-1). Significant results were confirmed in the entire cohort. CONCLUSIONS Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.
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Affiliation(s)
- Eva Cuzzoni
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Raffaella Franca
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, 34127, Italy
| | - Sara De Iudicibus
- Institute for Maternal Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Annalisa Marcuzzi
- Institute for Maternal Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marianna Lucafò
- Institute for Maternal Health - IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marco Pelin
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Diego Favretto
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, 34127, Italy
| | - Elena Monti
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola, Bologna, Italy
| | - William Morello
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Luciana Ghio
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Claudio La Scola
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola, Bologna, Italy
| | - Francesca Mencarelli
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola, Bologna, Italy
| | - Andrea Pasini
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola, Bologna, Italy
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Giuliana Decorti
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, 34127, Italy.
- Institute for Maternal Health - IRCCS "Burlo Garofolo", Trieste, Italy.
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste, Italy
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14
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Xuan J, Xiong Y, Shi L, Aramini B, Wang H. Do lncRNAs and circRNAs expression profiles influence discoid lupus erythematosus progression?-a comprehensive analysis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:728. [PMID: 32042744 DOI: 10.21037/atm.2019.12.10] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs)are involved in the progression of discoid lupus erythematosus (DLE), but an understanding of their underlying mechanisms remains elusive. To explore the expression profiles of lncRNAs and circRNAs in DLE, we surveyed the lncRNA/circRNA and mRNA expression profiles in the epithelia of oral DLE and adjacent normal tissues. Methods The lesional and non-lesional lower lips of three DLE patients were analysed by RNA-sequencing (RNA-seq). The principal functions of the significantly deregulated genes were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. And the correlated expression networks (coding-noncoding co-expression and lncRNAs-transcription factor-mRNA) were evaluated as well. Results Hundreds of significantly changed lncRNAs and mRNAs and dozens of significantly changed circRNAs were identified. lncRNA lnc-MIPOL1-6 and IncRNA IncDDX47-3 expressions were correlated with immune response-related genes, including IL19, CXCL1, CXCL11, and TNFSF15. Up-regulated IncRNA-TF network consists of 8 TFs and 74 related lncRNAs. The lncRNA-TF-gene trans-regulation consisting of 204 lncRNAs,39 TFs, and correlated 3 genes. Conclusions These results demonstrate that lncRNAs and circRNAs can influence the progression of DLE. Certain mRNAs/lncRNAs/circRNAs may have substantial value in DLE diagnosis and therapy.
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Affiliation(s)
- Jing Xuan
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Yaoyang Xiong
- Department of Prosthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.,Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China
| | - Linjun Shi
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China.,Department of Oral Mucosa Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Haiyan Wang
- Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai 200011, China.,Department of Oral Mucosa Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
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15
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Suresh V, Sundaram R, Dash P, Sabat SC, Mohapatra D, Mohanty S, Vasudevan D, Senapati S. Macrophage migration inhibitory factor of Syrian golden hamster shares structural and functional similarity with human counterpart and promotes pancreatic cancer. Sci Rep 2019; 9:15507. [PMID: 31664114 PMCID: PMC6820718 DOI: 10.1038/s41598-019-51947-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 10/07/2019] [Indexed: 12/12/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize the structure and function of Mesocricetus auratus MIF (MaMIF) and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant MaMIF was cloned, expressed and purified in a bacterial expression system. The MaMIF primary sequence, biochemical properties, and crystal structure analysis showed greater similarity with human MIF. The crystal structure of MaMIF illustrates that it forms a homotrimer as known in human and mouse. However, MaMIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that MaMIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of MaMIF into HapT1 pancreatic tumor-bearing hamsters significantly enhanced the tumor growth and tumor-associated angiogenesis. Together, the current study shows a structural and functional similarity between the hamster and human MIF. Moreover, it has demonstrated that a high level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.
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Affiliation(s)
- Voddu Suresh
- Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.,Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Rajivgandhi Sundaram
- Macromolecular Crystallography Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.,Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Pujarini Dash
- Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Surendra Chandra Sabat
- Molecular Biology of Abiotic Stress Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Debasish Mohapatra
- Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Sneha Mohanty
- Department of Microbiology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India
| | - Dileep Vasudevan
- Macromolecular Crystallography Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.
| | - Shantibhusan Senapati
- Tumor Microenvironment and Animal Models Lab, Institute of Life Sciences, Bhubaneswar, Odisha, India.
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16
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Liu A, Li H, Qi X, Wang Q, Yang B, Wu T, Yan N, Li Y, Pan Q, Gao Y, Gao L, Liu C, Zhang Y, Cui H, Li K, Wang Y, Wang X. Macrophage Migration Inhibitory Factor Triggers Inflammatory Responses During Very Virulent Infectious Bursal Disease Virus Infection. Front Microbiol 2019; 10:2225. [PMID: 31632367 PMCID: PMC6779731 DOI: 10.3389/fmicb.2019.02225] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 09/11/2019] [Indexed: 12/31/2022] Open
Abstract
Infectious bursal disease (IBD) is one of the main threats to the poultry industry worldwide. In China, very virulent IBD virus (vvIBDV) is the main prevalent virus strain, causing inflammation, immunosuppression, and high mortality in young chickens. To determine whether this acute inflammation can trigger lesions or even death in chickens, it is important to study the mechanism of vvIBDV pathogenicity. Thus, in the current study, we investigated the inflammation response, bursal lesions, and mortality in chickens caused by vvIBDV at different time points postinfection. Results showed an upregulation of proinflammatory cytokines, including interleukin-1β and interleukin-18, and macrophage infiltration in bursa in response to vvIBDV infection. High-throughput proteomic sequencing based on isobaric tags for relative and absolute quantitation showed that chicken macrophage migration inhibitory factor (chMIF) was upregulated uniquely in primary bursal cells infected with vvIBDV compared with infection by nonpathogenic attenuated IBDV. We confirmed that chMIF was upregulated by vvIBDV infection both in vivo and in vitro. Moreover, chMIF was extracellularly secreted by infected DT40 and primary bursal cells. Further experiments revealed that the secreted chMIF could induce migration of peripheral blood mononuclear cells and promote transcription of proinflammatory cytokines in chicken primary macrophages. Notably, these effects of chMIF could be reduced by using an MIF specific inhibitor. Thus, our study elucidates critical molecular determinants underlying vvIBDV-mediated initiation of acute inflammation, which might be pivotal to understand the mechanism of vvIBDV pathogenicity.
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Affiliation(s)
- Aijing Liu
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hui Li
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xiaole Qi
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Qi Wang
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Bo Yang
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Tiantian Wu
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Nana Yan
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yue Li
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Qing Pan
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yulong Gao
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Li Gao
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Changjun Liu
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yanping Zhang
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Hongyu Cui
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Kai Li
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yongqiang Wang
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xiaomei Wang
- Division of Avian Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
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17
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Bilsborrow JB, Doherty E, Tilstam PV, Bucala R. Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus. Expert Opin Ther Targets 2019; 23:733-744. [PMID: 31414920 DOI: 10.1080/14728222.2019.1656718] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with upstream regulatory roles in innate and adaptive immunity and is implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Several classes of MIF inhibitors such as small molecule inhibitors and peptide inhibitors are in clinical development. Areas covered. The role of MIF in the pathogenesis of RA and SLE is examined; the authors review the structure, physiology and signaling characteristics of MIF and the related cytokine D-DT/MIF-2. The preclinical and clinical trial data for MIF inhibitors are also reviewed; information was retrieved from PubMed and ClinicalTrials.gov using the keywords MIF, D-DT/MIF-2, CD74, CD44, CXCR2, CXCR4, Jab-1, rheumatoid arthritis, systemic lupus erythematosus, MIF inhibitor, small molecule, anti-MIF, anti-CD74, and peptide inhibitor. Expert opinion. Studies in mice and in humans demonstrate the therapeutic potential of MIF inhibition for RA and SLE. MIF- directed approaches could be particularly efficacious in patients with high expression MIF genetic polymorphisms. In patients with RA and SLE and high expression MIF alleles, targeted MIF inhibition could be a precision medicine approach to treatment. Anti-MIF pharmacotherapies could also be steroid-sparing in patients with chronic glucocorticoid dependence or refractory autoimmune disease.
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Affiliation(s)
- Joshua B Bilsborrow
- Department of Internal Medicine, Yale University School of Medicine , New Haven , CT , USA
| | - Edward Doherty
- Department of Internal Medicine, Yale University School of Medicine , New Haven , CT , USA
| | - Pathricia V Tilstam
- Department of Internal Medicine, Yale University School of Medicine , New Haven , CT , USA
| | - Richard Bucala
- Department of Internal Medicine, Yale University School of Medicine , New Haven , CT , USA
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18
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Strehl C, Ehlers L, Gaber T, Buttgereit F. Glucocorticoids-All-Rounders Tackling the Versatile Players of the Immune System. Front Immunol 2019; 10:1744. [PMID: 31396235 PMCID: PMC6667663 DOI: 10.3389/fimmu.2019.01744] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/10/2019] [Indexed: 12/13/2022] Open
Abstract
Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia.
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Affiliation(s)
- Cindy Strehl
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- German Rheumatism Research Centre (DRFZ) Berlin, Berlin, Germany
| | - Lisa Ehlers
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- German Rheumatism Research Centre (DRFZ) Berlin, Berlin, Germany
| | - Timo Gaber
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- German Rheumatism Research Centre (DRFZ) Berlin, Berlin, Germany
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- German Rheumatism Research Centre (DRFZ) Berlin, Berlin, Germany
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Macrophage Migration Inhibitory Factor Promotes the Interaction between the Tumor, Macrophages, and T Cells to Regulate the Progression of Chemically Induced Colitis-Associated Colorectal Cancer. Mediators Inflamm 2019; 2019:2056085. [PMID: 31360118 PMCID: PMC6652048 DOI: 10.1155/2019/2056085] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 06/11/2019] [Indexed: 12/16/2022] Open
Abstract
Colitis-associated colorectal cancer (CRC) development has been shown to be related to chronically enhanced inflammation. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that favors inflammatory cytokine production and has chemotactic properties for the recruitment of macrophages (Møs) and T cells. Here, we investigated the role of MIF in the inflammatory response and recruitment of immune cells in a murine model of chemical carcinogenesis to establish the impact of MIF on CRC genesis and malignancy. We used BALB/c MIF-knockout (MIF-/-) and wild-type (WT) mice to develop CRC by administering intraperitoneal (i.p.) azoxymethane and dextran sodium sulfate in drinking water. Greater tumor burdens were observed in MIF-/- mice than in WT mice. Tumors from MIF-/- mice were histologically identified to be more aggressive than tumors from WT mice. The localization of MIF suggests that it is also involved in cell differentiation. The relative gene expression of il-17, measured by real-time PCR, was higher in MIF-/- CRC mice, compared to the WT CRC and healthy MIF-/- mice. Importantly, compared to the WT intestinal epithelium, lower percentages of tumor-associated Møs were found in the MIF-/- intestinal epithelium. These results suggest that MIF plays a role in controlling the initial development of CRC by attracting Møs to the tumor, which is a condition that favors the initial antitumor responses.
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20
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Hie B, Cho H, DeMeo B, Bryson B, Berger B. Geometric Sketching Compactly Summarizes the Single-Cell Transcriptomic Landscape. Cell Syst 2019; 8:483-493.e7. [PMID: 31176620 PMCID: PMC6597305 DOI: 10.1016/j.cels.2019.05.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/12/2019] [Accepted: 05/07/2019] [Indexed: 12/21/2022]
Abstract
Large-scale single-cell RNA sequencing (scRNA-seq) studies that profile hundreds of thousands of cells are becoming increasingly common, overwhelming existing analysis pipelines. Here, we describe how to enhance and accelerate single-cell data analysis by summarizing the transcriptomic heterogeneity within a dataset using a small subset of cells, which we refer to as a geometric sketch. Our sketches provide more comprehensive visualization of transcriptional diversity, capture rare cell types with high sensitivity, and reveal biological cell types via clustering. Our sketch of umbilical cord blood cells uncovers a rare subpopulation of inflammatory macrophages, which we experimentally validated. The construction of our sketches is extremely fast, which enabled us to accelerate other crucial resource-intensive tasks, such as scRNA-seq data integration, while maintaining accuracy. We anticipate our algorithm will become an increasingly essential step when sharing and analyzing the rapidly growing volume of scRNA-seq data and help enable the democratization of single-cell omics.
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Affiliation(s)
- Brian Hie
- Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA
| | - Hyunghoon Cho
- Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA
| | - Benjamin DeMeo
- Department of Mathematics, MIT, Cambridge, MA 02139, USA; Department of Biomedical Informatics, Harvard University, Cambridge, MA 02138, USA
| | - Bryan Bryson
- Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Bonnie Berger
- Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Department of Mathematics, MIT, Cambridge, MA 02139, USA.
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21
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Soumoy L, Kindt N, Ghanem G, Saussez S, Journe F. Role of Macrophage Migration Inhibitory Factor (MIF) in Melanoma. Cancers (Basel) 2019; 11:cancers11040529. [PMID: 31013837 PMCID: PMC6520935 DOI: 10.3390/cancers11040529] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/05/2019] [Accepted: 04/10/2019] [Indexed: 12/11/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine involved in the carcinogenesis of many cancer types. Here, we review the published experimental and clinical data for MIF and its involvement in melanoma. All reported data show that MIF is overexpressed in melanoma cells, especially in case of metastatic disease. Clinical studies also indicate that high MIF expression is positively associated with aggressiveness of the disease. Some data also highlight the implication of MIF in angiogenesis, immunity and metastasis in melanoma cell lines, as well as the availability of different therapeutic options targeting MIF for the treatment of metastatic melanoma. Indeed, the main problem in metastatic melanoma is the lack of long-term effective treatment. This is linked to the capacity of melanoma cells to mutate very quickly and/or activate alternative signaling pathways. Thus, MIF targeting therapies could provide a new effective way of treating melanoma. Moreover, cell sensitivity to MIF depletion does not correlate with the BRAF mutational status. Regarding the fact that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after treatment with an inhibitor of the mutant BRAF protein.
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Affiliation(s)
- Laura Soumoy
- Department of Human Anatomy and Experimental Oncology, Université de Mons (UMons), Research Institute for Health Sciences and Technology, 7000 Mons, Belgium.
| | - Nadège Kindt
- Department of Human Anatomy and Experimental Oncology, Université de Mons (UMons), Research Institute for Health Sciences and Technology, 7000 Mons, Belgium.
| | - Ghanem Ghanem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium.
| | - Sven Saussez
- Department of Human Anatomy and Experimental Oncology, Université de Mons (UMons), Research Institute for Health Sciences and Technology, 7000 Mons, Belgium.
- Department of Oto-Rhino-Laryngology, Université Libre de Bruxelles (ULB), CHU Saint-Pierre, 1000 Brussels, Belgium.
| | - Fabrice Journe
- Department of Human Anatomy and Experimental Oncology, Université de Mons (UMons), Research Institute for Health Sciences and Technology, 7000 Mons, Belgium.
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1000 Brussels, Belgium.
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22
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Otrocka-Domagała I, Paździor-Czapula K, Gesek M. Dexamethasone-induced impairment of post-injury skeletal muscle regeneration. BMC Vet Res 2019; 15:56. [PMID: 30744624 PMCID: PMC6371463 DOI: 10.1186/s12917-019-1804-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 01/30/2019] [Indexed: 12/14/2022] Open
Abstract
Background Due to the routine use of dexamethasone (DEX) in veterinary and human medicine and its negative impact on the rate of wound healing and skeletal muscle condition, we decided to investigate the effect of DEX on the inflammatory and repair phases of skeletal muscle regeneration. In this study, a porcine skeletal muscle injury model was used. The animals were divided into non-treated and DEX-treated (0.2 mg/kg/day) groups. On the 15th day of DEX administration, bupivacaine hydrochloride-induced muscle injury was performed, and the animals were sacrificed in subsequent days. Regeneration was assessed by histopathology and immunohistochemistry. In the inflammatory phase, the presence and degree of extravasation, necrosis and inflammation were evaluated, while in the repair phase, the numbers of muscle precursor cells (MPCs), myotubes and young myofibres were estimated. Results In the inflammatory phase, DEX increased the severity and prolonged extravasation, prolonged necrosis and inflammation at the site of the muscle injury. In the repair phase, DEX delayed and prolonged MPC presence, impaired and prolonged myotube formation, and delayed young myofibre formation. Furthermore, DEX markedly affected the kinetics of the parameters of the inflammatory phase of the skeletal muscle regeneration more than that of the repair phase. Conclusions DEX impairment of the inflammatory and repair phases of the skeletal muscle regeneration was proven for the first time. The drug appears to affect the inflammatory phase more than the repair phase of regeneration. In light of our results, the possibility of reduction of the regenerative capacity of skeletal muscles should be considered during DEX therapy, and its use should be based on risk–benefit assessment.
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Affiliation(s)
- Iwona Otrocka-Domagała
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Street 13, 10-719, Olsztyn, Poland.
| | - Katarzyna Paździor-Czapula
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Street 13, 10-719, Olsztyn, Poland
| | - Michał Gesek
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Street 13, 10-719, Olsztyn, Poland
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Metry AM, Al Salmi I, Al Balushi F, Yousef MA, Al Ismaili F, Hola A, Hannawi S. Systemic Lupus Erythematosus: Symptoms and Signs at Initial Presentations. Antiinflamm Antiallergy Agents Med Chem 2019; 18:142-150. [PMID: 30488801 DOI: 10.2174/1871523018666181128161828] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/18/2018] [Accepted: 11/22/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem inflammatory condition that causes microvascular inflammation with the production of various auto-antibodies that play a major role in its pathogenesis. SLE can affect both sexes, all ages, and all ethnic groups with widespread geographical and socioeconomic backgrounds. Asia encompasses people of many sociocultural backgrounds with diverse ethnic. OBJECTIVE Due to a lack of national epidemiological research, the incidence and prevalence of SLE in Middle Eastern and Arab countries, have only recently been studied. This article aims to explore the status of SLE in Oman and to record symptoms and signs of SLE at first presentation. METHODOLOGY Medical records of all patients diagnosed with SLE at the Royal Hospital from 2006 to 2014 were reviewed for information recorded at first visit. SLE diagnosis was based on the American College of Rheumatology classification criteria; ACR97 (which includes the clinical manifestation and laboratory evidence). Patients with SLE disease manifestations extrapolated and analyzed. There were 966 patients diagnosed with SLE during the period from 2006 to 2014. Mean (SD) age at presentations was 35.5 (11.5) years. Majority of patients were female which constitutes 88.7% of the total SLE patients with mean age 27.6 (1.4) years. RESULTS Constitutional symptoms were found in 48.68 of SLE population including fatigue in 35.22%, and weight changes in 13.43%. The cutaneous manifestations that were present included malar rash 37.69%, photosensitivity 35.10%, discoid lupus 17.63%, and hair loss 39.29%. Musculoskeletal manifestations were commonly seen among the studied population including arthralgia in 68.75%, myalgia in 55.65%, arthritis in 48.31%, whilst myositis, tendon abnormalities and avascular necrosis were found in only 2.47%, 0.31% and 1.98%. respectively. CONCLUSION This is the first study of the symptoms and signs at initial clinical presentation of SLE patients compared to other studies done regionally where most have focused on clinical manifestations during the progression course of SLE. SLE manifestations may be related to the differences in the genetic make-up of the patients who come from various ethnic groups despite similar geography or sociocultural background, or to referral bias, as some studies were performed in the nephrology units and others in the rheumatology units. There is a pressing need to establish a nationwide and regional collaboration to establish LUPUS and to put forward a strategic planning with each MOH to provide an easy and efficient report of SLE cases and provide various effective management for such a debilitating syndrome.
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Affiliation(s)
| | - Issa Al Salmi
- The Renal Medicine Department, The Royal Hospital, Muscat, Oman
| | | | | | | | - Alan Hola
- The Renal Medicine Department, The Royal Hospital, Muscat, Oman
| | - Suad Hannawi
- Rheumatology Department, Ministry of Health and Prevention, Dubai 65522, United Arab Emirates
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24
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Vincent FB, Slavin L, Hoi AY, Kitching AR, Mackay F, Harris J, Kandane-Rathnayake R, Morand EF. Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus. Lupus Sci Med 2018; 5:e000277. [PMID: 30397495 PMCID: PMC6203042 DOI: 10.1136/lupus-2018-000277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/20/2018] [Accepted: 08/27/2018] [Indexed: 01/02/2023]
Abstract
Objective To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE). Methods MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score. Results uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K≥10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use. Conclusions These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal-specific SLE biomarker.
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Affiliation(s)
- Fabien B Vincent
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Laura Slavin
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Alberta Y Hoi
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Arthur Richard Kitching
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Fabienne Mackay
- Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.,Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - James Harris
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Rangi Kandane-Rathnayake
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Eric F Morand
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
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25
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Molecular mechanisms of glucocorticoid resistance in systemic lupus erythematosus: A review. Life Sci 2018; 209:383-387. [PMID: 30125579 DOI: 10.1016/j.lfs.2018.08.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/14/2018] [Accepted: 08/14/2018] [Indexed: 12/23/2022]
Abstract
The treatment of systemic lupus erythematosus (SLE) with glucocorticoids (GCs) is quite effective; however, GC resistance or insensitivity is a major barrier to the treatment of SLE. Therefore, it is necessary to identify the underlying mechanisms that lead to GC resistance. Much evidence shows that the mechanism of GC resistance is very complicated. GC receptor is involved in the main mechanism of GC resistance and was illustrated by a lot of literature. Therefore, this paper focuses on the GC resistance mechanisms of non-glucocorticoids receptor, including P-gp, MIF, TLR9, and Th17 cells. These molecular mechanisms may help diagnose GC resistance and provide an alternative treatment strategy to reverse GC resistance by blocking the underlying mechanisms.
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26
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Huang B, Jiang J, Luo B, Zhu W, Liu Y, Wang Z, Zhang Z. Non-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus. J Cell Mol Med 2018; 22:3330-3339. [PMID: 29570934 PMCID: PMC6010693 DOI: 10.1111/jcmm.13608] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 02/16/2018] [Indexed: 12/14/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, which results in various organ pathologies. However, current treatment towards SLE is suboptimal. Erythropoietin (EPO) has been shown to promote SLE recovery, but clinical application can be limited by its haematopoiesis-stimulating effects. EPO-derived helix-B peptide (ARA290) is non-erythrogenic but has been reported to retain the anti-inflammatory and tissue-protective functions of EPO. Therefore, here we investigated the effects and potential mechanisms of ARA290 on SLE. The administration of ARA290 to pristane-induced SLE and MRL/lpr mice significantly suppressed the level of serum antinuclear autoantibodies (ANAs) and anti-dsDNA autoantibodies, reduced the deposition of IgG and C3, and ameliorated the nephritis symptoms. Moreover, the serum concentrations of inflammatory cytokine IL-6, MCP-1 and TNF-α in SLE mice were reduced by ARA290. Further, ARA290 decreased the number of apoptotic cells in kidney. In vitro experiment revealed that ARA290 inhibited the inflammatory activation of macrophages and promoted the phagocytotic function of macrophages to apoptotic cells. Finally, ARA290 did not induce haematopoiesis during treatment. In conclusion, ARA290 ameliorated SLE, which at least could be partly due to its anti-inflammatory and apoptotic cell clearance promoting effects, without stimulating haematopoiesis, suggesting that ARA290 could be a hopeful candidate for SLE treatment.
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Affiliation(s)
- Bo Huang
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Juntao Jiang
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Bangwei Luo
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Wen Zhu
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Yuqi Liu
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Zhishang Wang
- Institute of ImmunologyArmy Medical UniversityChongqingChina
| | - Zhiren Zhang
- Institute of ImmunologyArmy Medical UniversityChongqingChina
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Shen D, Lang Y, Chu F, Wu X, Wang Y, Zheng X, Zhang HL, Zhu J, Liu K. Roles of macrophage migration inhibitory factor in Guillain-Barré syndrome and experimental autoimmune neuritis: beneficial or harmful? Expert Opin Ther Targets 2018; 22:567-577. [PMID: 29856236 DOI: 10.1080/14728222.2018.1484109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Macrophage migration inhibitory factor (MIF) plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN), which may offer an opportunity for the development of the novel therapeutic strategies for GBS. Areas covered: 'macrophage migration inhibitory factor' and 'Guillain-Barré syndrome' were used as keywords to search for related publications on Pub-Med, National Center for Biotechnology Information (NCBI), USA. MIF is involved in the etiology of various inflammatory and autoimmune disorders. However, the roles of MIF in GBS and EAN have not been summarized in the publications we identified. Therefore, in this review, we described and analyzed the major roles of MIF in GBS/EAN. Primarily, this molecule aggravates the inflammatory responses in this disorder. However, multiple studies indicated a protective role of MIF in GBS. The potential of MIF as a therapeutic target in GBS has been recently demonstrated in experimental and clinical studies, although clinical trials have been unavailable to date. Expert opinion: MIF plays a critical role in the initiation and progression of GBS and EAN, and it may represent a potential therapeutic target for GBS.
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Affiliation(s)
- Donghui Shen
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Yue Lang
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Fengna Chu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Xiujuan Wu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Ying Wang
- b Department of Neurobiology, Care Sciences and Society , Division of Neurodegeneration, Karolinska Institute, Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Xiangyu Zheng
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
| | - Hong-Liang Zhang
- c Department of Life Sciences , the National Natural Science Foundation of China , Beijing , China
| | - Jie Zhu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China.,b Department of Neurobiology, Care Sciences and Society , Division of Neurodegeneration, Karolinska Institute, Karolinska University Hospital Huddinge , Stockholm , Sweden
| | - Kangding Liu
- a Neuroscience Center, Department of Neurology , The First Hospital of Jilin University, Jilin University , Changchun , China
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28
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Illescas O, Gomez-Verjan JC, García-Velázquez L, Govezensky T, Rodriguez-Sosa M. Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum. Front Genet 2018; 9:55. [PMID: 29545822 PMCID: PMC5839154 DOI: 10.3389/fgene.2018.00055] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 02/06/2018] [Indexed: 12/13/2022] Open
Abstract
Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on MIF gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C MIF SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], P < 0.01; OR: 0.81 [0.74-0.89], P < 0.0001; and OR: 0.81 [0.76-0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], P < 0.01; OR: 0.66 [0.48-0.92], P < 0.0154; and OR: 0.70 [0.60-0.82], P < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], P < 0.0001; OR: 0.77 [0.72-0.83], P < 0.0001; OR: 0.61 [0.44-0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], P < 0.0001; OR: 0.80 [0.75-0.86], P < 0.0001; OR: 0.73 [0.63-0.85], P-value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.
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Affiliation(s)
- Oscar Illescas
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
| | - Juan C. Gomez-Verjan
- División de Investigación Básica, Instituto Nacional de Geriatría, Mexico City, Mexico
| | - Lizbeth García-Velázquez
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Tzipe Govezensky
- Departamento de Biología Molecular, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
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Wang X, Ma S, Wu H, Shen X, Xu S, Guo X, Bolick ML, Wu S, Wang F. Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition. Exp Mol Med 2018; 50:e445. [PMID: 29504609 PMCID: PMC5903823 DOI: 10.1038/emm.2017.271] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/25/2017] [Accepted: 09/12/2017] [Indexed: 12/21/2022] Open
Abstract
Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1. In cultured dopaminergic neurons, rMIF enhanced the recruitment of G9a and SUV39H1, followed by an increase in H3K9me2/H3K9me3. These molecular changes correspondingly exhibited alterations in Th promoter CpG site methylation and pain behaviors. In summary, MIF functions as a braking factor in curbing dopaminergic descending inhibition in peripheral nerve injury-induced hypersensitivity by mediating Th gene methylation through G9a/SUV39H1-associated H3K9 methylation.
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Affiliation(s)
- Xian Wang
- Department of Anesthesiology, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Shaolei Ma
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haibo Wu
- Department of Anesthesiology, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Xiaofeng Shen
- Department of Anesthesiology, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Shiqin Xu
- Department of Anesthesiology, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Xirong Guo
- Institute of Pediatrics, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China
| | - Maria L Bolick
- Group of Neuropharmacology and Neurophysiology, Division of Neuroscience, The Bonoi Academy of Science and Education, Chapel Hill, NC, USA
| | - Shizheng Wu
- Department of Neurology, Qinghai Provincial People's Hospital, Xining, China
| | - Fuzhou Wang
- Department of Anesthesiology, Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, China.,Group of Neuropharmacology and Neurophysiology, Division of Neuroscience, The Bonoi Academy of Science and Education, Chapel Hill, NC, USA
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30
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Shang ZB, Wang J, Kuai SG, Zhang YY, Ou QF, Pei H, Huang LH. Serum Macrophage Migration Inhibitory Factor as a Biomarker of Active Pulmonary Tuberculosis. Ann Lab Med 2018; 38:9-16. [PMID: 29071813 PMCID: PMC5700157 DOI: 10.3343/alm.2018.38.1.9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 05/10/2017] [Accepted: 09/20/2017] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine with chemokine-like functions, has been shown to play a central role in several acute and chronic inflammatory diseases. However, limited information is available regarding the use of MIF as an inflammatory pathway marker in patients with tuberculosis. This study aimed to investigate the association of MIF with IFN-γ and TNF-α in active pulmonary tuberculosis (APTB) following anti-tuberculosis treatment. METHODS The MIF, TNF-α, and IFN-γ serum levels were determined in 47 patients with APTB by cytokine-specific ELISA at four phases: prior to anti-tuberculosis drug treatment (baseline), and following 2, 4, and 6 months of treatment. In addition, we measured the MIF, TNF-α, and IFN-γ serum levels in 50 health controls. RESULTS MIF serum levels were significantly elevated (P<0.05) in patients with APTB prior to treatment compared with that in control subjects, and TNF-α ≥449.7 pg/mL was associated with high MIF levels (≥13.1 ng/mL). MIF levels were significantly reduced (P<0.01) following 2, 4, and 6 months of treatment, with variations in TNF-α and IFN-γ serum levels. MIF levels were positively correlated with the paired TNF-α level at baseline (r=0.1103, P=0.0316) and following 6 months of treatment (r=0.09569, P=0.0364). CONCLUSIONS A reduction in the MIF serum levels in patients with APTB following anti-tuberculosis treatment may positively affect host immune protection against Mycobacterium tuberculosis infection. Thus, serum MIF levels may constitute a useful marker for assessing therapy effectiveness in patients with APTB.
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Affiliation(s)
- Zhong Bo Shang
- Department of Clinical Laboratory, Wuxi Huishan People's Hospital, Wuxi, Jiangsu, China
| | - Jun Wang
- Department of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China
| | - Shou Gang Kuai
- Department of Clinical Laboratory, Wuxi Huishan People's Hospital, Wuxi, Jiangsu, China
- Department of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China.
| | - Yin Yin Zhang
- Department of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China
| | - Qin Fang Ou
- Department of Respiratory Medicine, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China
| | - Hao Pei
- Department of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China
| | - Li Hua Huang
- Department of Respiratory Medicine, The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu, China
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Tsou LK, Huang YH, Song JS, Ke YY, Huang JK, Shia KS. Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology. Med Res Rev 2017; 38:1188-1234. [PMID: 28768055 DOI: 10.1002/med.21464] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/13/2017] [Accepted: 07/16/2017] [Indexed: 12/12/2022]
Abstract
CXCR4 antagonists (e.g., PlerixaforTM ) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell-based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4-binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer-aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long-term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.
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Affiliation(s)
- Lun Kelvin Tsou
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | | | - Jen-Shin Song
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Yi-Yu Ke
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Jing-Kai Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Kak-Shan Shia
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
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Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function. Cytokine 2017; 99:214-224. [PMID: 28780379 DOI: 10.1016/j.cyto.2017.07.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/08/2017] [Accepted: 07/13/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS WT and Mif-/- BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-β (IL-β), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, Mif-/-STZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1β, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the Mif-/-STZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from Mif-/-STZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans.
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Fujihara Y, Hikita A, Takato T, Hoshi K. Roles of macrophage migration inhibitory factor in cartilage tissue engineering. J Cell Physiol 2017; 233:1490-1499. [PMID: 28574571 DOI: 10.1002/jcp.26036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/01/2017] [Indexed: 12/22/2022]
Abstract
To obtain stable outcomes in regenerative medicine, understanding and controlling immunological responses in transplanted tissues are of great importance. In our previous study, auricular chondrocytes in tissue-engineered cartilage transplanted in mice were shown to express immunological factors, including macrophage migration inhibitory factor (MIF). Since MIF exerts pleiotropic functions, in this study, we examined the roles of MIF in cartilage regenerative medicine. We made tissue-engineered cartilage consisting of auricular chondrocytes of C57BL/6J mouse, atellocollagen gel and a PLLA scaffold, and transplanted the construct subcutaneously in a syngeneic manner. Localization of MIF was prominent in cartilage areas of tissue-engineered cartilage at 2 weeks after transplantation, though it became less apparent by 8 weeks. Co-culture with RAW264 significantly increased the expression of MIF in chondrocytes, suggesting that the transplanted chondrocytes in tissue-engineered cartilage could enhance the expression of MIF by stimulation of surrounding macrophages. When MIF was added in the culture of chondrocytes, the expression of type II collagen was increased, indicating that MIF could promote the maturation of chondrocytes. Meanwhile, toluidine blue staining of constructs containing wild type (Mif+/+) chondrocytes showed increased metachromasia compared to MIF-knockout (Mif-/-) constructs at 2 weeks. However, this tendency was reversed by 8 weeks, suggesting that the initial increase in cartilage maturation in Mif+/+ constructs deteriorated by 8 weeks. Since the Mif+/+ constructs included more iNOS-positive inflammatory macrophages at 2 weeks, MIF might induce an M1 macrophage-polarized environment, which may eventually worsen the maturation of tissue-engineered cartilage in the long term.
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Affiliation(s)
- Yuko Fujihara
- Department of Oral-Maxillofacial Surgery and Orthodontics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.,Department of Cartilage and Bone Regeneration (Fujisoft), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Atsuhiko Hikita
- Department of Cartilage and Bone Regeneration (Fujisoft), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Tsuyoshi Takato
- Department of Oral-Maxillofacial Surgery and Orthodontics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.,Division of Tissue Engineering, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Kazuto Hoshi
- Department of Oral-Maxillofacial Surgery and Orthodontics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.,Division of Tissue Engineering, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
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Ryazanova MA, Fedoseeva LA, Ershov NI, Efimov VM, Markel AL, Redina OE. The gene-expression profile of renal medulla in ISIAH rats with inherited stress-induced arterial hypertension. BMC Genet 2016; 17:151. [PMID: 28105926 PMCID: PMC5249016 DOI: 10.1186/s12863-016-0462-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background The changes in the renal function leading to a reduction of medullary blood flow can have a great impact on sodium and water homeostasis and on the long-term control of arterial blood pressure. The RNA-Seq approach was used for transcriptome profiling of the renal medulla from hypertensive ISIAH and normotensive WAG rats to uncover the genetic basis of the changes underlying the renal medulla function in the ISIAH rats being a model of the stress-sensitive arterial hypertension and to reveal the genes which possibly may contribute to the alterations in medullary blood flow. Results Multiple DEGs specifying the function of renal medulla in ISIAH rats were revealed. The group of DEGs described by Gene Ontology term ‘oxidation reduction’ was the most significantly enriched one. The other groups of DEGs related to response to external stimulus, response to hormone (endogenous) stimulus, response to stress, and homeostatic process provide the molecular basis for integrated responses to homeostasis disturbances in the renal medulla of the ISIAH rats. Several DEGs, which may modulate the renal medulla blood flow, were detected. The reduced transcription of Nos3 pointed to the possible reduction of the blood flow in the renal medulla of ISIAH rats. Conclusions The generated data may be useful for comparison with those from different models of hypertension and for identifying the common molecular determinants contributing to disease manifestation, which may be potentially used as new pharmacological targets. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0462-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marina A Ryazanova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation
| | - Larisa A Fedoseeva
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation
| | - Nikita I Ershov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation
| | - Vadim M Efimov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
| | - Arcady L Markel
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.,Novosibirsk State University, Novosibirsk, Russian Federation
| | - Olga E Redina
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russian Federation.
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Zielińska KA, Van Moortel L, Opdenakker G, De Bosscher K, Van den Steen PE. Endothelial Response to Glucocorticoids in Inflammatory Diseases. Front Immunol 2016; 7:592. [PMID: 28018358 PMCID: PMC5155119 DOI: 10.3389/fimmu.2016.00592] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/29/2016] [Indexed: 12/16/2022] Open
Abstract
The endothelium plays a crucial role in inflammation. A balanced control of inflammation requires the action of glucocorticoids (GCs), steroidal hormones with potent cell-specific anti-inflammatory properties. Besides the classic anti-inflammatory effects of GCs on leukocytes, recent studies confirm that endothelial cells also represent an important target for GCs. GCs regulate different aspects of endothelial physiology including expression of adhesion molecules, production of pro-inflammatory cytokines and chemokines, and maintenance of endothelial barrier integrity. However, the regulation of endothelial GC sensitivity remains incompletely understood. In this review, we specifically examine the endothelial response to GCs in various inflammatory diseases ranging from multiple sclerosis, stroke, sepsis, and vasculitis to atherosclerosis. Shedding more light on the cross talk between GCs and endothelium will help to improve existing therapeutic strategies and develop new therapies better tailored to the needs of patients.
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Affiliation(s)
- Karolina A. Zielińska
- Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Laura Van Moortel
- Receptor Research Laboratories, Nuclear Receptor Lab, VIB-UGent, VIB Medical Biotechnology Center, Ghent, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Karolien De Bosscher
- Receptor Research Laboratories, Nuclear Receptor Lab, VIB-UGent, VIB Medical Biotechnology Center, Ghent, Belgium
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Kindt N, Journe F, Laurent G, Saussez S. Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets. Oncol Lett 2016; 12:2247-2253. [PMID: 27698786 DOI: 10.3892/ol.2016.4929] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/16/2016] [Indexed: 12/18/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) was originally identified in 1966 by Bloom and Bennett as a pro-inflammatory cytokine involved in the inhibition of macrophage motility. Since then, studies have investigated the functional contribution of this pro-inflammatory cytokine in several immune diseases, including rheumatoid arthritis and lupus erythematous. Recently, MIF has been reported to be involved in a variety of neoplastic diseases. The present review discusses previous cancer research studies that have investigated the involvement of MIF in carcinogenesis, disease prognosis, tumor cell proliferation and invasion, and tumor-induced angiogenesis. Finally, potential therapeutic approaches based on the use of MIF antagonists and neutralizing antibodies are examined. The review concludes that MIF could be a good prognostic biomarker in several types of cancer, but also that the inhibition of MIF could represent a novel therapy against cancer.
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Affiliation(s)
- Nadège Kindt
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, Mons 7000, Belgium
| | - Fabrice Journe
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, Mons 7000, Belgium; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Free University of Brussels, Brussels 1000, Belgium
| | - Guy Laurent
- Laboratory of Histology, Faculty of Medicine and Pharmacy, University of Mons, Mons 7000, Belgium
| | - Sven Saussez
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, Mons 7000, Belgium; Department of Otorhinolaryngology, Faculty of Medicine, Free University of Brussels, Brussels 1000, Belgium
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Georgouli M, Papadimitriou L, Glymenaki M, Patsaki V, Athanassakis I. Expression of MIF and CD74 in leukemic cell lines: correlation to DR expression destiny. Biol Chem 2016; 397:519-28. [PMID: 26866879 DOI: 10.1515/hsz-2015-0280] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 02/04/2016] [Indexed: 12/17/2022]
Abstract
Invariant chain (Ii) or CD74 is a non-polymorphic glycoprotein, which apart from its role as a chaperone dedicated to MHCII molecules, is known to be a high-affinity receptor for macrophage migration inhibitory factor (MIF). The present study aimed to define the roles of CD74 and MIF in the immune surveillance escape process. Towards this direction, the cell lines HL-60, Raji, K562 and primary pre-B leukemic cells were examined for expression and secretion of MIF. Flow cytometry analysis detected high levels of MIF and intracellular/membrane CD74 expression in all leukemic cells tested, while MIF secretion was shown to be inversely proportional to intracellular HLA-DR (DR) expression. In the MHCII-negative cells, IFN-γ increased MIF expression and induced its secretion in HL-60 and K562 cells, respectively. In K562 cells, CD74 (Iip33Iip35) was shown to co-precipitate with HLA-DOβ (DOβ), inhibiting thus MIF or DR binding. Induced expression of DOα in K562 (DOα-DOβ+) cells in different transfection combinations decreased MIF expression and secretion, while increasing surface DR expression. Thus, MIF could indeed be part of the antigen presentation process.
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The Role of Cellular Immune Responses on Chikungunya Virus Infection-Induced Arthritis. CURRENT TROPICAL MEDICINE REPORTS 2016. [DOI: 10.1007/s40475-016-0074-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Feng X, Chen W, Xiao L, Gu F, Huang J, Tsao BP, Sun L. Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus. Lupus 2016; 26:62-72. [PMID: 27230555 DOI: 10.1177/0961203316651738] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 04/28/2016] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Macrophage migration inhibitory factor (MIF) is a key regulator of both atherosclerosis and systemic lupus erythematosus (SLE), yet factors leading to its overproduction remain unclear. To explore regulation of MIF in SLE, we studied effects and potential mechanisms of type I interferon (IFN) and artesunate (ART), an antimalarial agent extracted from Chinese herbs, on levels of MIF. METHODS Serum and peripheral blood cells from SLE patients and healthy controls were measured for MIF levels by ELISA and type I IFN-inducible gene expressions by real-time PCR, respectively, and assessed for associations by Spearman correlation. ART was added to human umbilical vein endothelial cell (HUVEC) cultures with or without prior IFNα-1b stimulation and to SLE peripheral blood mononuclear cell (PBMC) cultures. Protein levels of STATs and phosphorylated (p-) STATs in HUVECs were determined by Western blotting. RESULTS Serum MIF levels were elevated in SLE patients and positively associated with disease activity (r = 0.86, p < 0.0001), accumulated damage (r = 0.34, p < 0.05), and IFN scores in SLE PBMCs (r = 0.74, p = 0.0002). The addition of IFNα-1b promoted MIF production in a time- and dose-dependent manner in HUVEC cultures. ART could inhibit expressions of IFN-inducible genes (LY6E and ISG15) in both HUVEC and SLE PBMC cultures, and suppress MIF production and over-expression of p-STAT1, but not p-STAT3 or STAT5, induced by IFNα-1b stimulation. IFNγ-induced expression of p-STAT1 in HUVECs was not inhibited by ART. CONCLUSION MIF could be regulated by type I IFN in SLE patients. ART counteracts the effect of IFNα to inhibit MIF production by blocking STAT1 phosphorylation and thus may have therapeutic potential for SLE-associated atherosclerosis.
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Affiliation(s)
- X Feng
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - W Chen
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - L Xiao
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - F Gu
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - J Huang
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - B P Tsao
- Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - L Sun
- Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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Merched AJ, Daret D, Li L, Franzl N, Sauvage-Merched M. Specific autoantigens in experimental autoimmunity-associated atherosclerosis. FASEB J 2016; 30:2123-34. [PMID: 26891734 DOI: 10.1096/fj.201500131] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/01/2016] [Indexed: 12/22/2022]
Abstract
Higher cardiovascular morbidity in patients with a wide range of autoimmune diseases highlights the importance of autoimmunity in promoting atherosclerosis. Our purpose was to investigate the mechanisms of accelerated atherosclerosis and identified vascular autoantigens targeted by autoimmunity. We created a mouse model of autoimmunity-associated atherosclerosis by transplanting bone marrow from FcγRIIB knockout (FcRIIB(-/-)) mice into LDL receptor knockout mice. We characterized the cellular and molecular mechanisms of atherogenesis and identified specific aortic autoantigens using serologic proteomic studies. En face lesion area analysis showed more aggressive atherosclerosis in autoimmune mice compared with control mice (0.64 ± 0.12 vs 0.32 ± 0.05 mm(2); P < 0.05, respectively). At the cellular level, FcRIIB(-/-) macrophages showed significant reduction (46-72%) in phagocytic capabilities. Proteomic analysis revealed circulating autoantibodies in autoimmune mice that targeted 25 atherosclerotic lesion proteins, including essential components of adhesion complex, cytoskeleton, and extracellular matrix, and proteins involved in critical functions and pathways. Microscopic examination of atherosclerotic plaques revealed essential colocalization of autoantibodies with endothelial cells, their adherence to basement membranes, the internal elastica lamina, and necrotic cores. The new vascular autoimmunosome may be a useful target for diagnostic and immunotherapeutic interventions in autoimmunity-associated diseases that have accelerated atherosclerosis.-Merched, A. J., Daret, D., Li, L., Franzl, N., Sauvage-Merched, M. Specific autoantigens in experimental autoimmunity-associated atherosclerosis.
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Affiliation(s)
- Aksam J Merched
- Department of Pharmaceutical Sciences, and INSERM U1053, University of Bordeaux, Bordeaux, France Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Danièle Daret
- Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Lan Li
- Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Nathalie Franzl
- Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
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Galvão I, Dias ACF, Tavares LD, Rodrigues IPS, Queiroz-Junior CM, Costa VV, Reis AC, Ribeiro Oliveira RD, Louzada-Junior P, Souza DG, Leng L, Bucala R, Sousa LP, Bozza MT, Teixeira MM, Amaral FA. Macrophage migration inhibitory factor drives neutrophil accumulation by facilitating IL-1β production in a murine model of acute gout. J Leukoc Biol 2016; 99:1035-43. [PMID: 26868525 DOI: 10.1189/jlb.3ma0915-418r] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 01/25/2016] [Indexed: 12/25/2022] Open
Abstract
This study evaluated the role of macrophage migration inhibitory factor in inflammation caused by monosodium urate crystals. The concentration of macrophage migration inhibitory factor was increased in synovial fluid of patients with acute gout, and there was a positive correlation between intra-articular macrophage migration inhibitory factor and IL-1β concentrations. In mice, the injection of monosodium urate crystals into the knee joint increased the levels of macrophage migration inhibitory factor in macrophages and in inflamed tissue. The injection of recombinant macrophage migration inhibitory factor into the joint of mice reproduced the inflammatory response observed in acute gout, including histologic changes, the recruitment of neutrophils, and increased levels of IL-1β and CXCL1. Importantly, the accumulation of neutrophils and the amount IL-1β in the joints were reduced in macrophage migration inhibitory factor-deficient mice when injected with monosodium urate crystals. We observed a similar effect when we blocked macrophage migration inhibitory factor with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid or anti-macrophage migration inhibitory factor. In addition, the blockade of IL-1R and CXCR2 reduced recombinant macrophage migration inhibitory factor-induced neutrophil recruitment. Mechanistically, recombinant macrophage migration inhibitory factor is important for the synthesis of il1β mRNA in vivo and in isolated macrophages. Altogether, macrophage migration inhibitory factor promotes neutrophil accumulation and is important for IL-1β production, which are 2 crucial events contributing to the pathogenesis of acute gout.
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Affiliation(s)
- Izabela Galvão
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Carolina Fialho Dias
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Livia Duarte Tavares
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Irla Paula Stopa Rodrigues
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Celso Martins Queiroz-Junior
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Vivian Vasconcelos Costa
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Alesandra Corte Reis
- Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Paulo Louzada-Junior
- Division of Rheumatology, School of Medicine of Ribeirao Preto, Universidade de São Paulo, Brazil
| | - Daniele Glória Souza
- Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Lin Leng
- Department of Medicine/Rheumatology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut, USA
| | - Richard Bucala
- Department of Medicine/Rheumatology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut, USA
| | - Lirlândia Pires Sousa
- Department of Clinical Analysis and Toxicological, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marcelo Torres Bozza
- Laboratory of Inflammation and Immunity, Department of Immunology, Institute of Microbiology, Universidade Federal do Rio de Janeiro, Brazil
| | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Flávio Almeida Amaral
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Luo JY, Xu R, Li XM, Zhou Y, Zhao Q, Liu F, Chen BD, Ma YT, Gao XM, Yang YN. MIF Gene Polymorphism rs755622 Is Associated With Coronary Artery Disease and Severity of Coronary Lesions in a Chinese Kazakh Population: A Case-Control Study. Medicine (Baltimore) 2016; 95:e2617. [PMID: 26825917 PMCID: PMC5291587 DOI: 10.1097/md.0000000000002617] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Inflammation plays an important role in the pathogenesis of atherosclerosis. Recent studies indicate that macrophage migration inhibitory factor (MIF) is a potent proinflammatory cytokine which mediates the inflammatory process during atherosclerosis. The polymorphism of MIF gene (rs755622 [-173G/C], rs1007888, and rs2096525) were genotyped by TaqMan single nucleotide polymorphism (SNP) genotyping assay in 320 patients with coronary artery disease (CAD) and 603 controls in a Chinese Kazakh population. Coronary angiography was performed on all CAD patients and Gensini score was used to assess the severity of coronary artery lesions. The frequency of the CC genotype and C allele of rs755622 were significantly higher in CAD patients than that in control subjects (8.4% vs. 5.1%, P < 0.001, 30.3% vs. 22.1%, P < 0.001, respectively). Multivariate logistic regression analysis showed that individuals with CC genotype or C allele had a higher risk for CAD (CC genotype vs. GG genotype, OR = 2.224, 95% CI, 1.239-3.992, P = 0.007, and C allele vs. G allele, OR = 1.473, 95% CI, 1.156-1.876, P = 0.002, respectively). Moreover, CAD patients with rs755622 C allele (CC + CG genotype) have higher levels of Gensini score when compared to C allele noncarriers (32.74 ± 26.66 vs. 21.44 ± 19.40, P < 0.001, adjusted). Our results suggested that the CC genotype and C allele of MIF rs755622 SNP may be a genetic marker for the risk of CAD and potentially predict the severity of CAD in Chinese Kazakh population.
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Affiliation(s)
- Jun-Yi Luo
- From the Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China (J-YL, X-ML, YZ, QZ, Y-TM, Y-NY); Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, Xinjiang, China (J-YL, X-ML, FL, B-DC, Y-TM, X-MG, Y-NY); Department of Cadres Health, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (RX); Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China (X-MG); Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (X-MG); and Department of Surgery, Central Clinical School, Monash University, Melbourne, Victoria, Australia (X-MG)
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Sánchez-Zamora YI, Juarez-Avelar I, Vazquez-Mendoza A, Hiriart M, Rodriguez-Sosa M. Altered Macrophage and Dendritic Cell Response in Mif-/- Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes. J Diabetes Res 2016; 2016:7053963. [PMID: 27699180 PMCID: PMC5028830 DOI: 10.1155/2016/7053963] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 07/10/2016] [Indexed: 12/13/2022] Open
Abstract
Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif-/- or wild-type (Wt) BALB/c mice. We found that Mif-/- mice treated with STZ (Mif-/-STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif-/-STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif-/-STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif-/-STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM.
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Affiliation(s)
- Yuriko Itzel Sánchez-Zamora
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Imelda Juarez-Avelar
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | | | - Marcia Hiriart
- Departamento de Neurodesarrollo y Fisiología, Instituto de Fisiología Celular, UNAM, 04510 Coyoacán, MEX, Mexico
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
- *Miriam Rodriguez-Sosa:
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Yang H, Zheng S, Mao Y, Chen Z, Zheng C, Li H, Sumners C, Li Q, Yang P, Lei B. Modulating of ocular inflammation with macrophage migration inhibitory factor is associated with notch signalling in experimental autoimmune uveitis. Clin Exp Immunol 2015; 183:280-93. [PMID: 26400205 DOI: 10.1111/cei.12710] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 09/11/2015] [Accepted: 09/22/2015] [Indexed: 12/29/2022] Open
Abstract
The aim of this study was to examine whether macrophage migration inhibitory factor (MIF) could exaggerate inflammatory response in a mouse model of experimental autoimmune uveitis (EAU) and to explore the underlying mechanism. Mutant serotype 8 adeno-associated virus (AAV8) (Y733F)-chicken β-actin (CBA)-MIF or AAV8 (Y733F)-CBA-enhanced green fluorescent protein (eGFP) vector was delivered subretinally into B10.RIII mice, respectively. Three weeks after vector delivery, EAU was induced with a subcutaneous injection of a mixture of interphotoreceptor retinoid binding protein (IRBP) peptide with CFA. The levels of proinflammatory cytokines were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Retinal function was evaluated with electroretinography (ERG). We found that the expression of MIF and its two receptors CD74 and CD44 was increased in the EAU mouse retina. Compared to AAV8.CBA.eGFP-injected and untreated EAU mice, the level of proinflammatory cytokines, the expression of Notch1, Notch4, delta-like ligand 4 (Dll4), Notch receptor intracellular domain (NICD) and hairy enhancer of split-1 (Hes-1) increased, but the ERG a- and b-wave amplitudes decreased in AAV8.CBA.MIF-injected EAU mice. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) reduced the expression of NICD, Hes-1 and proinflammatory cytokines. Further, a MIF antagonist ISO-1 attenuated intraocular inflammation, and inhibited the differentiation of T helper type 1 (Th1) and Th17 in EAU mice. We demonstrated that over-expression of MIF exaggerated ocular inflammation, which was associated with the activation of the Notch signalling. The expression of both MIF and its receptors are elevated in EAU mice. Over-expression of MIF exaggerates ocular inflammation, and this exaggerated inflammation is associated with the activation of the Notch signalling and Notch pathway. Our data suggest that the MIF-Notch axis may play an important role in the pathogenesis of EAU. Both the MIF signalling pathways may be promising targets for developing novel therapeutic interventions for uveitis.
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Affiliation(s)
- H Yang
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
| | - S Zheng
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
| | - Y Mao
- School of Biotechnology, Southern Medical University, Guangzhou, China
| | - Z Chen
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
| | - C Zheng
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
| | - H Li
- School of Biotechnology, Southern Medical University, Guangzhou, China
| | - C Sumners
- Department of Physiology and Functional Genomics and McKnight Brain Institute, Gainesville, FL, USA
| | - Q Li
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - P Yang
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
| | - B Lei
- Department of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China
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Kuai SG, Ou QF, You DH, Shang ZB, Wang J, Liu J, Zhou XK, Pei H, Huang LH. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor (MIF) are associated with active pulmonary tuberculosis. Infect Dis (Lond) 2015; 48:222-8. [PMID: 26542751 DOI: 10.3109/23744235.2015.1107188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE The role of the cytokine, macrophage migration inhibition factor (MIF) was assessed in tuberculosis. This case-control study investigated whether commonly occurring functional MIF polymorphisms are associated with active tuberculosis as well as with serum levels of MIF, IFN-γ and TNF-α. METHODS Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173G/C single-nucleotide polymorphism (rs755622), were analysed by PCR and PCR-RFLP, respectively, in 47 patients and 50 healthy subjects. The mRNA level of MIF was performed by real-time PCR (RT-PCR), and MIF, IFN-γ and TNF-α serum levels were determined by ELISA. RESULTS A significant increase of MIF mRNA expression and MIF protein level were found in patients compared to healthy controls. Meanwhile, the increase of IFN-γ and TNF-α serum levels were confirmed. According to the profile of genetic model, a significant association was found of genotypes carrying the -794 CATT 7 or 8 and -173 C risk alleles with susceptibility to active tuberculosis and with a significant increase of MIF, IFN-γ and TNF-α. CONCLUSIONS These data suggested a distinct genetic and immunopathogenic basis for tuberculosis at the MIF locus. Serum MIF, IFN-γ and TNF-α profiles distinguish tuberculosis from the more inflammatory phenotype and may play a role in pathogenesis and as biomarkers of active tuberculosis.
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Affiliation(s)
- Shou-Gang Kuai
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Qin-Fang Ou
- b Department of Respiratory Medicine , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - De-Hong You
- c Department of Clinical Laboratory , Wuxi Eighth People's Hospital , Wuxi , Jiangsu , PR China
| | - Zhong-Bo Shang
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Jun Wang
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Jun Liu
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Xi-Ke Zhou
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Hao Pei
- a Department of Clinical Laboratory , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
| | - Li-Hua Huang
- b Department of Respiratory Medicine , Wuxi Fifth People's Hospital, Jiangnan University , Wuxi , Jiangsu , PR China
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Wigren M, Nilsson J, Kaplan MJ. Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention. J Intern Med 2015; 278:494-506. [PMID: 25720452 PMCID: PMC4550575 DOI: 10.1111/joim.12357] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.
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Affiliation(s)
- M Wigren
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - J Nilsson
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
| | - M J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives. Front Immunol 2015; 6:429. [PMID: 26347749 PMCID: PMC4543903 DOI: 10.3389/fimmu.2015.00429] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 08/07/2015] [Indexed: 12/19/2022] Open
Abstract
CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus) and human β3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.
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Affiliation(s)
- Lukas Pawig
- Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University , Aachen , Germany
| | - Christina Klasen
- Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen , Germany
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich , Munich , Germany ; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich , Germany ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht , Netherlands
| | - Jürgen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen , Germany ; August-Lenz-Stiftung, Institute for Cardiovascular Research, Ludwig-Maximilians-University Munich , Munich , Germany
| | - Heidi Noels
- Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University , Aachen , Germany
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Macrophage immigration inhibitory factor promotes cell proliferation and inhibits apoptosis of cervical adenocarcinoma. Tumour Biol 2015; 36:5095-102. [DOI: 10.1007/s13277-015-3161-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/26/2015] [Indexed: 01/08/2023] Open
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Rojas J, Salazar J, Martínez MS, Palmar J, Bautista J, Chávez-Castillo M, Gómez A, Bermúdez V. Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis. SCIENTIFICA 2015; 2015:851252. [PMID: 26491604 PMCID: PMC4600540 DOI: 10.1155/2015/851252] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/09/2015] [Indexed: 05/15/2023]
Abstract
Cardiovascular disease (CVD) is a global epidemic, currently representing the worldwide leading cause of morbidity and mortality. Atherosclerosis is the fundamental pathophysiologic component of CVD, where the immune system plays an essential role. Monocytes and macrophages are key mediators in this aspect: due to their heterogeneity and plasticity, these cells may act as either pro- or anti-inflammatory mediators. Indeed, monocytes may develop heterogeneous functional phenotypes depending on the predominating pro- or anti-inflammatory microenvironment within the lesion, resulting in classic, intermediate, and non-classic monocytes, each with strikingly differing features. Similarly, macrophages may also adopt heterogeneous profiles being mainly M1 and M2, the former showing a proinflammatory profile while the latter demonstrates anti-inflammatory traits; they are further subdivided in several subtypes with more specialized functions. Furthermore, macrophages may display plasticity by dynamically shifting between phenotypes in response to specific signals. Each of these distinct cell profiles is associated with diverse biomarkers which may be exploited for therapeutic intervention, including IL-10, IL-13, PPAR-γ, LXR, NLRP3 inflammasomes, and microRNAs. Direct modulation of the molecular pathways concerning these potential macrophage-related targets represents a promising field for new therapeutic alternatives in atherosclerosis and CVD.
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Affiliation(s)
- Joselyn Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
- Endocrinology Department, Maracaibo University Hospital, Maracaibo 4004, Venezuela
- *Joselyn Rojas:
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - María Sofía Martínez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jim Palmar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Alexis Gómez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Valmore Bermúdez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
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Richard V, Kindt N, Decaestecker C, Gabius HJ, Laurent G, Noël JC, Saussez S. Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep 2014; 32:523-9. [PMID: 24939415 PMCID: PMC4091881 DOI: 10.3892/or.2014.3272] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/09/2014] [Indexed: 11/21/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) and its receptor CD74 appear to be involved in tumorigenesis. We evaluated, by immunohistochemical staining, the tissue expression and distribution of MIF and CD74 in serial sections of human invasive breast cancer tumor specimens. The serum MIF level was also determined in breast cancer patients. We showed a significant increase in serum MIF average levels in breast cancer patients compared to healthy individuals. MIF tissue expression, quantified by a modified Allred score, was strongly increased in carcinoma compared to tumor-free specimens, in the cancer cells and in the peritumoral stroma, with fibroblasts the most intensely stained. We did not find any significant correlation with histoprognostic factors, except for a significant inverse correlation between tumor size and MIF stromal positivity. CD74 staining was heterogeneous and significantly decreased in cancer cells but increased in the surrounding stroma, namely in lymphocytes, macrophages and vessel endothelium. There was no significant variation according to classical histoprognostic factors, except that CD74 stromal expression was significantly correlated with triple-negative receptor (TRN) status and the absence of estrogen receptors. In conclusion, our data support the concept of a functional role of MIF in human breast cancer. In addition to auto- and paracrine effects on cancer cells, MIF could contribute to shape the tumor microenvironment leading to immunomodulation and angiogenesis. Interfering with MIF effects in breast tumors in a therapeutic perspective remains an attractive but complex challenge. Level of co-expression of MIF and CD74 could be a surrogate marker for efficacy of anti-angiogenic drugs, particularly in TRN breast cancer tumor.
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Affiliation(s)
- Vincent Richard
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, B-7000 Mons, Belgium
| | - Nadège Kindt
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, B-7000 Mons, Belgium
| | - Christine Decaestecker
- Laboratory of Image, Signal Processing and Acoustics, Ecole Polytechnique de Bruxelles, B-1050 Brussels, Belgium
| | - Hans-Joachim Gabius
- Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig Maximilians University, D-80539 Munich, Germany
| | - Guy Laurent
- Laboratory of Histology, Faculty of Medicine and Pharmacy, University of Mons, B-7000 Mons, Belgium
| | | | - Sven Saussez
- Laboratory of Anatomy and Cellular Biology, Faculty of Medicine and Pharmacy, University of Mons, B-7000 Mons, Belgium
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