Richard Bucala

Bio: Richard Bucala is an academic researcher from Yale University. The author has contributed to research in topics: Macrophage migration inhibitory factor & Cytokine. The author has an hindex of 119, co-authored 595 publications receiving 54607 citations. Previous affiliations of Richard Bucala include École Polytechnique Fédérale de Lausanne & Rockefeller University.

The "Infodemic" of COVID-19.

Abstract: Some in the medical publishing world have observed an "infodemic" occurring alongside the pandemic. One might define an infodemic as a contagious disease infecting our information culture. As the Editors of A&R, tasked with conducting, reviewing, reporting, and translating science to the rheumatic disease community, we agree with this diagnosis. Herein, we reflect on how the pandemic has impacted A&R, the medical publishing world, and how we may best engage our community to navigate current challenges.

MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis

Abstract: Fibroblast-like synoviocytes mediate joint destruction in rheumatoid arthritis and exhibit sustained proinflammatory and invasive properties. CD44 is a polymorphic transmembrane protein with defined roles in matrix interaction and tumor invasion that is also a signaling coreceptor for macrophage migration inhibitory factor (MIF), which engages cell surface CD74. High-expression MIF alleles (rs5844572) are associated with rheumatoid joint erosion, but whether MIF signaling through the CD74/CD44 receptor complex promotes upstream autoimmune responses or contributes directly to synovial joint destruction is unknown. We report here the functional regulation of CD44 by an autocrine pathway in synovial fibroblasts that is driven by high-expression MIF alleles to up-regulate an inflammatory and invasive phenotype. MIF increases CD44 expression, promotes its recruitment into a functional signal transduction complex, and stimulates alternative exon splicing, leading to expression of the CD44v3-v6 isoforms associated with oncogenic invasion. CD44 recruitment into the MIF receptor complex, downstream MAPK and RhoA signaling, and invasive phenotype require MIF and CD74 and are reduced by MIF pathway antagonists. These data support a functional role for high-MIF expression alleles and the two-component CD74/CD44 MIF receptor in rheumatoid arthritis and suggest that pharmacologic inhibition of this pathway may offer a specific means to interfere with progressive joint destruction.

Plasma concentrations of macrophage migration inhibitory factor are elevated in Pima Indians compared to Caucasians and are associated with insulin resistance

Abstract: migration inhibitory factor are elevated in Pima Indians compared to Caucasians and are associated with insulin resistance concentrations, and acute insulin response (AIR 25-g intravenous glucose tolerance test) between Pima Indians and Caucasians (data not shown). Insulin action (M, hyperinsulinaemic euglycaemic clamp [7]) was lower in Pima Indians compared to Caucasians (3.75±1.18 and 4.72±1.79 mg·kgEMBS–1·min–1, respectively, p<0.05). While in these healthy subjects, MIF was frequently below the detection level of the assay, the frequency distribution of MIF in Pima Indians was different from Caucasians (Fig. 1A) with higher fasting MIF concentrations in Pima Indians (Wilcoxon Rank sum test p=0.04). Thus fasting MIF concentrations were higher than 5 ng/ml in 39% of Pima Indians, but not in any of the Caucasians. Fasting MIF was below the level of detection of the assay in 71% of Caucasians, 54% of Pima Indians (Fig. 1A). MIF concentrations at 2-h tended to be higher in Pima Indians compared to Caucasians (Wilcoxon Rank sum test p=0.1). There was no difference between fasting and 2-h MIF concentrations (p=0.2). Fasting MIF concentrations were negatively associated with M before (Fig. 1B) and after adjustment for age, sex and percentage of body fat (r=–0.80, p=0.0001). Moreover, those subjects who had undetectable fasting MIF concentrations had on average higher M values compared to those who had detectable fasting MIF concentrations (4.7±1.5 and 3.1±0.7 mg·kgEMBS–1·min–1, respectively, p=0.0005). 2-h MIF concentrations were not correlated with M (r=–0.06, p=0.9). There was no correlation between fasting or 2-h MIF and measures of adiposity (body fat and BMI), fasting and 2-h glucose and insulin and AIR before or after adjustment for age and sex (all p>0.05). Another study [4] showed that serum MIF concentrations were higher in patients with Type II diabetes compared to their age and sex matched normal healthy control subjects. We extend this observation by showing higher MIF concentrations in non-diabetic Pima Indians, a population at high risk for the development of Type II diabetes, compared to non-diabetic Caucasians. A study carried out in isolated rat islets showed that MIF production is regulated by glucose [3]. Despite this, we show that MIF concentrations are not associated with fasting glucose, a finding in agreement with a previous study [4], and additionally find no association between serum concentrations of MIF and 2 h plasma glucose. MIF has also been proposed to act in a paracrine fashion to modulate insulin secretion. Thus, in vitro immunoneutralization of MIF was shown to reduce insulin secretion [3]. However, we show that MIF concentrations are not associated with fasting or 2-h insulin and acute insulin secretory response. By contrast, we show that fasting MIF concentrations are strongly associated with insulin resistance in vivo. Associations of insulin resistance and MIF in healthy human subjects have not been reported, although MIF is released Diabetologia (2002) 45:1739–1741 DOI 10.1007/s00125-002-0896-4

Role of Macrophage Migration Inhibitory Factor in the Regulatory T Cell Response of Tumor-Bearing Mice

Abstract: Macrophage migration inhibitory factor (MIF) is involved in tumorigenesis by facilitating tumor proliferation and evasion of apoptosis; however, its role in tumor immunity is unclear. In this study, we investigated the effect of MIF on the progression of the syngenic, CT26 colon carcinoma and the generation of tumor regulatory T cells (Tregs). The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF(-/-)) mice than in wild-type (MIF(+/+)) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF(-/-) mice had significantly lower levels of tumor-associated CD4(+)Tregs than MIF(+/+) mice. The splenic cells of MIF(-/-) mice also showed a decrease in CD8(+)Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity. Interestingly, the inducible Treg response in spleen cells to anti-CD3/CD28 plus IL-2 plus TGF-β was greater in MIF(-/-) mice than in MIF(+/+) mice. Spleen cells of MIF(-/-) mice, stimulated with anti-CD3/CD28, produced lower levels of IL-2, but not TGF-β, than those of MIF(+/+) mice, which was recovered by the addition of recombinant MIF. Conversely, a neutralizing anti-MIF Ab blocked anti-CD3-induced IL-2 production by splenocytes of MIF(+/+) mice and suppressed the inducible Treg generation. Moreover, the administration of IL-2 into tumor-bearing MIF(-/-) mice restored the generation of Tregs and tumor growth. Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers.

Rat mesangial cells express macrophage migration inhibitory factor in vitro and in vivo.

Abstract: Mesangial cells are thought to promote glomerular macrophage accumulation in glomerulonephritis. This may occur through the production of macrophage migration inhibitory factor (MIF), a molecule known to regulate macrophage accumulation at sites of inflammation. To study this, glomerular MIF expression and macrophage accumulation were examined in rat anti-Thy-1 disease, a model of mesangioproliferative nephritis. In situ hybridization and immunohistochemistry showed that MIF is expressed by some podocytes in normal rat glomeruli. De novo MIF expression by glomerular endothelium was seen on day 1 of anti-Thy-1 disease. On day 6, glomerular MIF mRNA and protein expression were prominent in segmental proliferative lesions, which was also the location of most infiltrating macrophages. Double-staining identified de novo MIF mRNA and protein expression by proliferating mesangial cells within these lesions. Cytokine regulation of mesangial cell MIF expression was examined in vitro. Northern blotting showed that cultured rat mesangial cells express a single 0.6-kb species of MIF mRNA, and Western blotting detected a single protein band of 12.5 kD. Six-hour stimulation of mesangial cells with interferon-gamma or platelet-derived growth factor significantly increased MIF mRNA levels. However, the addition of recombinant MIF to mesangial cells did not affect mesangial cell proliferation or constitutive transforming growth factor-beta mRNA expression, nor did MIF induce monocyte chemoattractant protein-1 mRNA expression. In conclusion, this is the first study to demonstrate that mesangial cells can produce MIF in vivo and in vitro. It is postulated that mesangial cell MIF production in response to injury acts to promote macrophage accumulation within segmental proliferative lesions in rat anti-Thy-1 nephritis.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Multilineage Potential of Adult Human Mesenchymal Stem Cells

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。