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.

Reversal of established rat crescentic glomerulonephritis by blockade of macrophage migration inhibitory factor (MIF): potential role of MIF in regulating glucocorticoid production.

Abstract: Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine that also counter-regulates glucocorticoid action. We investigated whether immunoneutralization of MIF could reverse established experimental crescentic glomerulonephritis and if this treatment could modulate endogenous glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six littermate pairs of rats. Once crescentic disease was established on day 7, one animal in each pair was given a daily injection of neutralizing anti-MIF antibody (Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In addition, a group of 6 animals was killed on day 7 of disease without any treatment. Animals receiving the control Ab exhibited a rapidly progressive glomerulonephritis with severe renal injury (proteinuria), loss of renal function (creatinine clearance), anemia, and marked histologic damage (including glomerular crescent formation), compared with animals killed on day 7 without treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by restoring normal renal function and reducing histological damage compared with untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab treatment also prevented severe anemia (p < 0.05). Reversal of disease was associated with a significant reduction in leukocyte infiltration and activation and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment caused a significant increase in endogenous serum corticosterone levels, which correlated with the reversal of disease parameters. In conclusion, this study has demonstrated that blocking MIF activity can partially reverse established crescentic glomerulonephritis and suggests that MIF operates by both enhancing the cellular immune response and suppressing the endogenous anti-inflammatory glucocorticoid response.

Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease.

Abstract: The Semaphorins (Semas) are a family of highly conserved, secreted or membrane-bound proteins that are divided into eight classes based on primary sequence similarity and distinct structural features (1, 2). Semas are expressed on nerve, myeloid, and lymphoid cells, and they regulate immune responses as well as developmental processes related to organogenesis, angiogenesis, apoptosis, and neoplasia (3–5). Semaphorin 7a (Sema-7a), also called CDw108, is a GPI-anchored membrane protein that signals through at least two receptors: the β1-integrin subunit and Plexin C1 (1, 3). Sema-7a-mediated activation of β1-integrin enhances central and peripheral axonal growth and is requiredfor proper axonal tracking during embryonic development (4, 5), while Plexin C1 appears to inhibit some of these β1 integrin-mediated effects (3). Interactions between Sema-7a and its receptors also contribute to inflammation and immunity by stimulation of macrophage chemotaxis and cytokine production (6), regulation of dendritic cell migration and chemokine expression (4), modulation of T cell function (7), and regulation of melanocyte spreading and melanoma invasion (3, 8). Our recent studies advance the understanding of Sema-7a by demonstrating that it also plays an important role in the pathogenesis of transforming growth factor (TGF)-β1 induced inflammation and fibrosis (9). However, the mechanism(s) by which Sema-7a promotes these outcomes remains obscure. The CD14+ fraction of peripheral blood contains a heterogeneous group of monocyte progenitors with important roles in tissue injury and repair. A CD34+CD45+ subpopulation of CD14+ monocytes differentiates into fibrocytes by acquiring a fibroblast-like morphology and expressing collagens I and III (10). These events occur in a TGF-β1-dependent, PI3 kinase-dependent manner (11, 12), and over time, CD14 and CD34 expression may be down-regulated. Fibrocytes traffic into and accumulate in injured tissue in response to chemokines (13, 14), and their presence is associated with various fibrosing disorders including asthma, pulmonary fibrosis, and scleroderma (15–17). Interestingly, while Sema-7a is known to affect monocyte activation in vitro via β1 integrin mediated effects (6) the role of Sema-7a in the development of fibrocytes has not been assessed. Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disease characterized by progressive cutaneous and visceral fibrosis and over-activation of TGF-β1 signaling pathways (18, 19). Advances in the treatment of SSc-related renal disease have led to the emergence of pulmonary involvement as the greatest cause of mortality in SSc (20). The majority of patients with SSc demonstrate pathologic findings of interstitial lung disease (SSc-ILD) and show replacement of the normal lung parenchyma with inflamed and fibrotic tissue that is ineffective for gas exchange (21, 22). Up to 42% of patients with SSc-ILD will die of disease progression within ten years of diagnosis (20). Treatment with cyclophosphamide (23) or lymphocyte modulating agents (24, 25) show a modest benefit in delaying disease progression, but patients often relapse. The prevalence of gastroesophageal reflux disease (GERD) and ongoing autoimmunity in these patients frequently leads to poor outcomes following lung transplantation (26, 27). Thus, a better understanding of the pathogenesis of SSc-ILD may ameliorate the most frequent cause of death in these patients. We hypothesized that Sema-7a promotes TGF-β1-induced pulmonary fibrosis by stimulating the accumulation of intrapulmonary fibrocytes and that the β1 integrin subunit plays an important role in these responses. Fibrocytes have emerged as an important area of research in SSc-ILD (28). However immunologic factors regulating their accumulation remain obscure, and a role for Sema-7a has not been considered. We characterized the role of Sema-7a in fibrocyte accumulation in lung-targeted, TGF-β1 transgenic mice and defined the tissue compartment and molecular pathway through which Sema-7a exerts these effects. Our studies demonstrate that TGF-β1 induces fibrocyte accumulation in a Sema-7a dependent manner, that Sema-7a expression on bone marrow derived cells is sufficient for the induction of fibrosis and fibrocyte appearance, and that β1 integrin blockade ameliorates these responses. This signaling axis and pathway for fibrocyte activation exists in normal human cells and appears enhanced in patients with SSc-ILD.

Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise

Abstract: Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 (Tph2) and brain-derived neurotrophic factor (Bdnf) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif−/− mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain.

Macrophage Migration Inhibitory Factor Deletion Exacerbates Pressure Overload–Induced Cardiac Hypertrophy Through Mitigating Autophagy

Abstract: The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be cardioprotective under various pathological conditions. However, the underlying mechanisms still remain elusive. In this study, we revealed that MIF deficiency overtly exacerbated abdominal aorta constriction-induced cardiac hypertrophy and contractile anomalies. MIF deficiency interrupted myocardial autophagy in hypertrophied hearts. Rapamycin administration mitigated the exacerbated hypertrophic responses in MIF(-/-) mice. Using the phenylephrine-induced hypertrophy in vitro model in H9C2 myoblasts, we confirmed that MIF governed the activation of AMP-activated protein kinase-mammalian target of rapamycin-autophagy cascade. Confocal microscopic examination demonstrated that MIF depletion prevented phenylephrine-induced mitophagy in H9C2 myoblasts. Myocardial Parkin, an E3 ubiquitin ligase and a marker for mitophagy, was significantly upregulated after sustained pressure overload, the effect of which was prevented by MIF knockout. Furthermore, our data exhibited that levels of MIF, AMP-activated protein kinase activation, and autophagy were elevated concurrently in human failing hearts. These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses.

Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis.

Abstract: This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.

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。