Richard Bucala

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (350)1981.12 Total impact

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    ABSTRACT: Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the USA . The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate viral-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterise the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR and FACS. Alphaviral-infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. Reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex analysis, PPS treatment significantly increased the anti-inflammatory cytokine interleukin-10 and reduced pro-inflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus induced arthritis acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis. The hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas with approximately 1-million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently there is no licenced specific treatment for alphavirus disease and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects and is currently licensed under the name Elmiron® for the treatment of cystitis in the USA. Our findings show RRV infection damages the articular cartilage including a loss of proteoglycans within joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting PPS is a promising candidate for drug-repurposing for the treatment of alphavirus-induced arthritis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 05/2015; 89(15). DOI:10.1128/JVI.00224-15 · 4.65 Impact Factor
  • Maor Sauler · Richard Bucala · Patty J Lee
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    ABSTRACT: The prevalence of many common respiratory disorders, including pneumonia, Chronic Obstructive Lung Disease, pulmonary fibrosis and lung cancer increases with age. Little is known of the host factors that may predispose individuals to such diseases. Macrophage Migration Inhibitory Factor (MIF) is a potent upstream regulator of the immune system. MIF is encoded by variant alleles that occur commonly in the population. In addition to its role as a pro-inflammatory cytokine, a growing body of literature demonstrates that MIF influences diverse molecular processes important for the maintenance of cellular homeostasis, and may influence the incidence or clinical manifestations of a variety of chronic diseases. This review highlights the biologic properties of MIF and its implication in age-related lung disease. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 05/2015; DOI:10.1152/ajplung.00339.2014 · 4.04 Impact Factor
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    ABSTRACT: Mortality from pneumococcal pneumonia remains high despite antibiotic therapy, highlighting the pathogenic potential for host inflammation. We demonstrate that macrophage migration inhibitory factor (MIF), an innate immune mediator, is detrimental for survival as well as lung pathology, inflammatory cellular infiltration, and bacterial burden in a mouse model of pneumococcal pneumonia despite being necessary for clearance from the nasopharynx. Treatment of animals with a small molecule inhibitor of MIF improves survival by reducing inflammation and improving bacterial control. Our work demonstrates that MIF modulates beneficial vs. detrimental inflammatory responses in the host-pneumococcal interaction and is a potential target for therapeutic modulation. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:
    The Journal of Infectious Diseases 05/2015; DOI:10.1093/infdis/jiv262 · 5.78 Impact Factor
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    ABSTRACT: The rising number of obese individuals has become a major burden to the healthcare systems worldwide. Obesity includes not only the increase of adipose tissue mass but importantly also the altered cellular functions that collectively lead to a chronic state of adipose tissue inflammation, insulin resistance and impaired wound healing. Adipose tissue undergoing chronic inflammation shows altered cytokine expression and an accumulation of adipose tissue macrophages (ATM). The macrophage migration inhibitory factor (MIF) superfamily consists of MIF and the recently identified homolog D-dopachrome tautomerase (D-DT or MIF-2). MIF and D-DT, which both bind to the CD74/CD44 receptor complex, are differentially expressed in adipose tissue and have distinct roles in adipogenesis. MIF positively correlates with obesity as well as insulin resistance and contributes to adipose tissue inflammation by modulating ATM functions. D-DT, however, is negatively correlated with obesity and reverses glucose intolerance. In this review, their respective roles in adipose tissue homeostasis, adipose tissue inflammation, insulin resistance and impaired wound healing will be reviewed.
    05/2015; 47(5):e161. DOI:10.1038/emm.2015.26
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    ABSTRACT: The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity which contributes to MIF’s biological functional activity. In this study, we investigated the effects of blocking the hydrophobic active site of MIF’s tautomerase activity in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumour growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif/P1G). Primary tumour growth was significantly attenuated in both Mif-KO and Mif/P1G mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for MIF’s tautomerase enzymatic active site. From primary and secondary screens, the inhibitor, SCD-19 was identified which significantly attenuated MIF’s tautomerase enzymatic activity in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumour inoculation, was found to significantly reduce primary tumour volume by 90% (p<0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumour was palpable (at day 7, post-tumour inoculation) and again, treatment was found to significantly reduce tumour volume by 81% p<0.001) compared with the control treatment. In this paper, we identify a novel inhibitor which blocks the hydrophobic pocket of MIF, which houses it’s specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in in vivo systems.
    Molecular Medicine 04/2015; 20(1):729-735. DOI:10.2119/molmed.2014.00136 · 4.82 Impact Factor
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    Richard Bucala · Idit Shachar
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    ABSTRACT: Molecules that link innate and adaptive immunity and regulate immune response in health and disease are now the focus of many studies. This review discusses CD74 and its ligand macrophage migration inhibitory factor (MIF), and their central position in linking these two components of the immune response by controlling survival of macrophages and B cells.
    Mini Reviews in Medicinal Chemistry 02/2015; 14(14). · 3.19 Impact Factor
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cytokine 01/2015; 72(2):135-145. DOI:10.1016/j.cyto.2014.11.015 · 2.87 Impact Factor
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    ABSTRACT: Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif(-/-)), CD74-deficient (Cd74(-/-)) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif(-/-) and Cd74(-/-) mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif(-/-) mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.-Sauler, M., Zhang, Y., Min, J.-n., Leng, L., Shan, P., Roberts, S., Jorgensen, W. L., Bucala, R., Lee, P. J. Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury. © FASEB.
    The FASEB Journal 01/2015; 29(5). DOI:10.1096/fj.14-260299 · 5.48 Impact Factor
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    ABSTRACT: The study examined Hypothalamus-Pituitary-Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self-reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro-endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.
    Developmental Psychobiology 01/2015; 57(1). DOI:10.1002/dev.21265 · 3.16 Impact Factor
  • Bin Wu · Yang Song · Lin Leng · Richard Bucala · Liang-Jing Lu
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    ABSTRACT: This paper aims to explore the cost-effectiveness of reduced doses or discontinuation of etanercept biosimilar (Yisaipu) in patients with moderately active rheumatoid arthritis (RA). A discrete event simulation model was developed to project lifetime medical costs and quality-adjusted life-years (QALYs) in moderately active RA. Strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week, 25 mg/week or MTX maintenance were compared. Resource consumptions related to RA were estimated from the perspective of the Chinese health care system. An endpoint of the American College of Rheumatology (ACR) response was used to estimate the utility scores. Uncertainty in model parameters was analysed by sensitivity analyses. When using ACR as an endpoint for determining successful treatment, strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week or 25 mg/week maintenance showed the greatest number of QALYs gained (nearly 11.9 and 11.3 with or without rituximab after the failure of Yisaipu, respectively). If decision makers use a threshold of 3×the per capita GDP of China or Shanghai City in 2012, then the strategies most likely to be cost-effective are initial treatment with Yisaipu 50 mg/week for nine months following MTX maintenance and Yisaipu 25 mg/week maintenance, respectively. Results were sensitive to the cost of Yisaipu. The analysis indicates that, in China, replacing branded etanercept with Yisaipu is likely to be a cost-effective strategy in patients with moderately active RA.
    Clinical and experimental rheumatology 12/2014; 33(1). · 2.97 Impact Factor
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    ABSTRACT: Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM. SAMs dynamically regulate HSC activation and ECM degradation. To gain insight into the role of MIF in progression of liver fibrosis, we investigated markers of fibrosis and immune responses after chronic CCl4 administration to female C57BL/6 and MIF(-/-) mice. Chronic CCl4 exposure increased activation of HSC in WT mice, indicated by increased expression of αSMA mRNA and protein, as well as mRNA for collagen 1α1; these responses were blunted in female MIF(-/-) mice. Despite lower activation of HSC in MIF(-/-) mice, accumulation of ECM was similar in WT and MIF(-/-)mice, suggesting a decreased rate of ECM degradation. Recruitment of SAMs was lower in MIF(-/-) mice compared with WT mice, both in their initial inflammatory phenotype, as well as in the later phase as proresolution macrophages. The decreased presence of resolution macrophages was associated with lower expression of MMP13 in MIF(-/-) mice. Taken together, these data indicate that MIF-dependent recruitment of SAMs contributes to degradation of ECM via MMP13, highlighting the importance of appropriate recruitment and phenotypic profile of macrophages in the resolution of fibrosis.
    Journal of Leukocyte Biology 11/2014; 97(1). DOI:10.1189/jlb.3A0614-280R · 4.30 Impact Factor
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    ABSTRACT: Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators’ expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissect the role of MIF derived from different cellular sources in post-MI cardiac remodelling, we generated chimeric mice with MIF deficiency either in bone marrow derived-cells (WTKO) or in somatic-cells (KOWT). Compared to WT and KOWT mice, WTKO mice had reduced rupture risk and ameliorated cardiac remodelling, associated with attenuated regional leukocyte infiltration and expression of inflammatory mediators. In contrast, KOWT mice had delayed healing and enhanced expression of M1 macrophage markers, but diminished expression of M2 markers during the early healing phase. In conclusion, global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation. Leukocyte-derived MIF promotes inflammatory responses after MI, whereas cardiac-derived MIF affects early but not ultimate healing process.
    Journal of Molecular and Cellular Cardiology 10/2014; 69. DOI:10.1016/j.yjmcc.2014.01.015 · 5.22 Impact Factor
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    ABSTRACT: We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar Ki's, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF. These inhibitors were also found to selectively inhibit interactions between PfMIF and the human MIF receptor CD74. The results of this study provide the framework for the development of new therapeutics that target PfMIF.
    Journal of Medicinal Chemistry 09/2014; 57(20). DOI:10.1021/jm501168q · 5.48 Impact Factor
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    ABSTRACT: Author Summary Uncontrolled inflammation is a major contributor to pathogenicity development during many chronic parasitic infections, including African trypanosome infections. Hence, therapies should aim at re-establishing the balance between pro- and anti-inflammatory responses to reduce tissue damage. Our experiments uncovered that macrophage migration inhibitory factor (MIF) plays a pivotal role in trypanosomiasis-associated pathogenicity development. Hereby, MIF-deficient and neutralizing anti-MIF antibody-treated wild type (WT) T. brucei-infected mice exhibited decreased inflammatory responses, reduced liver damage and anemia (i.e. the most prominent pathogenicity features) compared to WT control mice. The reduced tissue damage coincided with reduced infiltration of pathogenic monocytic cells and neutrophils, whereby neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to tissue damage. MIF also promoted anemia development by suppressing red blood cell production and enhancing their clearance. The clinical significance of these findings follows from human genetic data indicating that low-expression (protective) MIF alleles are enriched in Africans. The current findings therefore offer promise for human translation and open the possibility of assessing MIF levels or MIF genotype as an indication of an individual's risk for severe trypanosomiasis. Furthermore, given the unmet medical need of African trypanosomiasis affecting millions of people, these findings highlight MIF as a potential new therapeutic target for treatment of trypanosomiasis-associated pathogenicity.
    PLoS Pathogens 09/2014; 10(9):e1004414. DOI:10.1371/journal.ppat.1004414 · 8.14 Impact Factor
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    ABSTRACT: MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-)mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.-Heinrichs, D., Berres, M.-L., Coeuru, M., Knauel, M., Nellen, A., Fischer, P., Philippeit, C., Bucala, R., Trautwein, C., Wasmuth, H. E., Bernhagen, J. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.
    The FASEB Journal 08/2014; 28(12). DOI:10.1096/fj.14-256776 · 5.48 Impact Factor
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    ABSTRACT: Objectives: Glucocorticoids remain a mainstay of the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the potential for therapies that regulate glucocorticoid sensitivity to enable glucocorticoid dose reduction. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein implicated in the pathogenesis of RA, which also impairs glucocorticoid sensitivity via inhibition of the MAP kinase phosphatase, MKP-1. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We therefore investigated whether GILZ is implicated in regulation of glucocorticoid sensitivity by MIF.Methods: GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MAP kinase phosphatase-1 (MKP-1) studied at the level of expression and function.Results: GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3a. GILZ was shown to regulate the expression of MKP-1, and consequent MAP kinase phosphorylation and cytokine release.Conclusions: MIF exerts its effects on MKP-1 expression and MAP kinase activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected intersection between these two molecules and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity. © 2014 American College of Rheumatology.
    Arthritis and Rheumatology 08/2014; 66(8). DOI:10.1002/art.38689
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    ABSTRACT: We report a new inflammatory activity for extracellular d-dopachrome tautomerase (D-DT), the recruitment of neutrophils to the lung on D-DT intratracheal installation of C57BL/6J mice with an EC50 of 5.6 μg. We also find that D-DT and macrophage migration inhibitory factor (MIF) have additive effects in neutrophil recruitment. Although the tautomerase site of D-DT and its homologue MIF are biophysically very different, 4-iodo-6-phenylpyrimidine (4-IPP) forms a covalent bond with Pro-1 of both proteins, resulting in a 6-phenylpyrimidine (6-PP) adduct. Recruitment of neutrophils to the lung for the 6-PP adducts of D-DT and MIF are reduced by ∼50% relative to the apo proteins, demonstrating that an unmodified Pro-1 is important for this activity, but there is no cooperativity in inhibition of the proteins together. The differences in the binding mode of the 6-PP adduct for D-DT was determined by crystallographic studies at 1.13 Å resolution and compared to the structure of the MIF-6-PP complex. There are major differences in the location of the 6-PP adduct to the D-DT and MIF active sites that provide insight into the lack of cooperativity by 4-IPP and into tuning the properties of the covalent inhibitors of D-DT and MIF that are necessary for the development of therapeutic small molecules against neutrophil damage from lung infections such as Pseudomonas aeruginosa in cystic fibrosis and immunocompromised patients.-Rajasekaran, D., Zierow, S., Syed, M., Bucala, R., Bhandari, V., Lolis, E. J. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment.
    The FASEB Journal 07/2014; 28(11). DOI:10.1096/fj.14-256636 · 5.48 Impact Factor
  • PD Njobvu · S Trollip · J Chipeta · R Bucala · P McGill
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    ABSTRACT: The cellular response to stress involves the recruitment and coordination of molecular signaling pathways that prevent cell death. D-dopachrome tautomerase (DDT) is an enzyme that lacks physiologic substrates in mammalian cells, but shares partial sequence and structural homology with macrophage migration inhibitory factor (MIF). Here, we observed that DDT is highly expressed in murine cardiomyocytes and secreted by the heart after ischemic stress. Antibody-dependent neutralization of secreted DDT exacerbated both ischemia-induced cardiac contractile dysfunction and necrosis. We generated cardiomyocyte-specific DDT knockout mice (Myh6-Cre Ddtfl/fl), which demonstrated normal baseline cardiac size and function, but had an impaired physiologic response to ischemia-reperfusion. Hearts from Myh6-Cre Ddtfl/fl mice exhibited more necrosis and LV contractile dysfunction than control hearts after coronary artery ligation and reperfusion. Furthermore, treatment with DDT protected isolated hearts against injury and contractile dysfunction after ischemia-reperfusion. The protective effect of DDT required activation of the metabolic stress enzyme AMP-activated protein kinase (AMPK), which was mediated by a CD74/CaMKK2-dependent mechanism. Together, our data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.
    Journal of Clinical Investigation 07/2014; 124(8). DOI:10.1172/JCI73061 · 13.77 Impact Factor
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    ABSTRACT: Neuronal apoptosis is one of the major causes of poststroke neurological deficits. Inflammation during the acute phase of stroke results in nuclear translocation of NFκB in affected cells in the infarct area. Macrophage migration inhibitory factor (MIF) promotes cardiomyocyte survival in mice following heart ischemia. However, the role of MIF during stroke remains limited. In this study, we showed that MIF expression is down-regulated by 0.75 ± 0.10-fold of the control in the infarct area in the mouse brains. Two functional cis-acing NFκB response elements were identified in the human MIF promoter. Dual activation of hypoxia and NFκB signaling resulted in significant reduction of MIF promoter activity to 0.86 ± 0.01-fold of the control. Furthermore, MIF reduced caspase-3 activation and protected neurons from oxidative stress- and in vitro ischemia/reperfusion-induced apoptosis. H2O2 significantly induced cell death with 12.81 ± 0.58-fold increase of TUNEL-positive cells, and overexpression of MIF blocked the H2O2-induced cell death. Disruption of the MIF gene in MIF-knockout mice resulted in caspase-3 activation, neuronal loss, and increased infarct development during stroke in vivo. The infarct volume was increased from 6.51 ± 0.74% in the wild-type mice to 9.07 ± 0.66% in the MIF-knockout mice. Our study demonstrates that MIF exerts a neuronal protective effect and that down-regulation of MIF by NFκB-mediated signaling under hypoxia accelerates neuronal loss during stroke. Our results suggest that MIF is an important molecule for preserving a longer time window for stroke treatment, and strategies to maintain MIF expression at physiological level could have beneficial effects for stroke patients.-Zhang, S., Zis, O., Ly, P. T. T., Wu, Y., Zhang, S., Zhang, M., Cai, F., Bucala, R., Shyu, W.-C., Song, W. Down-regulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke.
    The FASEB Journal 06/2014; 28(10). DOI:10.1096/fj.14-253625 · 5.48 Impact Factor

Publication Stats

17k Citations
1,981.12 Total Impact Points


  • 2003–2015
    • Yale-New Haven Hospital
      • • Department of Laboratory Medicine
      • • Department of Pathology
      New Haven, Connecticut, United States
    • The Ohio State University
      Columbus, Ohio, United States
  • 1995–2015
    • Yale University
      • • Department of Internal Medicine
      • • School of Medicine
      • • Section of Rheumatology
      New Haven, Connecticut, United States
    • New York Medical College
      New York, New York, United States
    • Nara Medical University
      • Department of Internal Medicine
      Kashihara, Nara, Japan
  • 2013
    • Jilin University
      • Department of Pharmacology
      Yung-chi, Jilin Sheng, China
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
  • 2012
    • Rutgers, The State University of New Jersey
      Нью-Брансуик, New Jersey, United States
  • 2003–2012
    • University of Louisville
      • Division of Medical Oncology and Hematology
      Louisville, Kentucky, United States
  • 2010
    • Weizmann Institute of Science
      • Department of Immunology
  • 2009
    • Sun Yat-Sen University
      Shengcheng, Guangdong, China
  • 2008
    • Centro Internacional de Entrenamiento e Investigaciones Médicas
      Santiago de Cali, Valle del Cauca, Colombia
  • 2007
    • Henan Provincial People’s Hospital
      Cheng, Henan Sheng, China
  • 2006
    • Hokkaido University
      • Department of Medicine II
      Sapporo-shi, Hokkaido, Japan
  • 2005
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
    • Kurume University
      • Division of Nephrology
      Куруме, Fukuoka, Japan
  • 1984–2005
    • The Rockefeller University
      • Laboratory of Investigative Dermatology
      New York City, New York, United States
  • 2004
    • Hokuriku University
      Kanazawa, Ishikawa, Japan
  • 1999–2004
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • Louisiana State University Health Sciences Center New Orleans
      New Orleans, Louisiana, United States
  • 2002
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 1998
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Burke Medical Research Institute New York
      New York, New York, United States
    • Tufts University
      Бостон, Georgia, United States
  • 1996
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York City, New York, United States
  • 1985
    • CUNY Graduate Center
      New York City, New York, United States