More Than Just a Removal Service:Scavenger Receptors in Leukocyte Trafficking

Scavenger receptors are a highly diverse superfamily of proteins which are grouped by their inherent ability to bind and internalize a wide array of structurally diverse ligands which can be either endogenous or exogenous in nature. Consequently, scavenger receptors are known to play important roles in host homeostasis, with common endogenous ligands including apoptotic cells, and modified low density lipoproteins (LDLs); additionally, scavenger receptors are key regulators of inflammatory diseases, such as atherosclerosis. Also, as a consequence of their affinity for a wide range of microbial products, their role in innate immunity is also being increasingly studied. However, in this review, a secondary function of a number of endothelial-expressed scavenger receptors is discussed. There is increasing evidence that some endothelial-expressed scavenger receptors are able to directly bind leukocyte-expressed ligands and subsequently act as adhesion molecules in the trafficking of leukocytes in lymphatic and vascular tissues. Here, we cover the current literature on this alternative role for endothelial-expressed scavenger receptors and also speculate on their therapeutic potential

Prognostic Value and Potential Immunoregulatory Role of SCARF1 in Hepatocellular Carcinoma

Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4(+) T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4(+) T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4(+) T cells (CD4(+)CD25(−)) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration

Commensal-derived OMVs elicit a mild proinflammatory response in intestinal epithelial cells

Under normal physiological conditions, the intestinal immunity remains largely hyporesponsive to the commensal microbiota, yet also retains the inherent ability to rapidly respond to pathogenic antigens. However, immunomodulatory activities of extracellular products from commensal bacteria have been little studied, with previous investigations generally utilising the live bacterium to study microbiota-epithelial interactions. In this study, we demonstrate that extracellular products of a commensal bacterium, Escherichia coli C25, elicit a moderate release of proinflammatory IL-8 and stimulate transcriptional up-regulation of Toll-like receptors (TLRs) in intestinal epithelial cell lines, HT29-19A and Caco-2. Additionally, we show that removal of outer membrane vesicles (OMVs) diminishes the proinflammatory effect of secreted products from E. coli C25. Furthermore, we show that isolated OMVs have a dose-dependent proinflammatory effect on IECs. Interestingly, a relatively high concentration (10x culture concentration) of OMVs had no significant regulatory effects on TLR mRNA expression in both cell lines. Finally, we also demonstrate a that pre-incubation with E. coli C25-derived OMVs subsequently inhibited the internalisation of the bacterium itself in both cell lines. Taken together, our results suggest that commensal-derived extracellular products, in particular OMVs, could significantly contribute to intestinal homeostasis. We also demonstrate a unique interaction between commensal-derived OMVs and host cells

Excited-State Lifetimes of DNA-Templated Cyanine Dimer, Trimer, and Tetramer Aggregates: The Role of Exciton Delocalization, Dye Separation, and DNA Heterogeneity

DNA-templated molecular (dye) aggregates are a novel class of materials that have garnered attention in a broad range of areas including light harvesting, sensing, and computing. Using DNA to template dye aggregation is attractive due to the relative ease with which DNA nanostructures can be assembled in solution, the diverse array of nanostructures that can be assembled, and the ability to precisely position dyes to within a few Angstroms of one another. These factors, combined with the programmability of DNA, raise the prospect of designer materials custom tailored for specific applications. Although considerable progress has been made in characterizing the optical properties and associated electronic structures of these materials, less is known about their excited-state dynamics. For example, little is known about how the excited-state lifetime, a parameter essential to many applications, is influenced by structural factors, such as the number of dyes within the aggregate and their spatial arrangement. In this work, we use a combination of transient absorption spectroscopy and global target analysis to measure excited-state lifetimes in a series of DNA-templated cyanine dye aggregates. Specifically, we investigate six distinct dimer, trimer, and tetramer aggregates—based on the ubiquitous cyanine dye Cy5—templated using both duplex and Holliday junction DNA nanostructures. We find that these DNA-templated Cy5 aggregates all exhibit significantly reduced excited-state lifetimes, some by more than 2 orders of magnitude, and observe considerable variation among the lifetimes. We attribute the reduced excited-state lifetimes to enhanced nonradiative decay and proceed to discuss various structural factors, including exciton delocalization, dye separation, and DNA heterogeneity, that may contribute to the observed reduction and variability of excited-state lifetimes. Guided by insights from structural modeling, we find that the reduced lifetimes and enhanced nonradiative decay are most strongly correlated with the distance between the dyes. These results inform potential tradeoffs between dye separation, excitonic coupling strength, and excited-state lifetime that motivate deeper mechanistic understanding, potentially via further dye and dye template design

Ultracool Field Brown Dwarf Candidates Selected at 4.5 microns

We have identified a sample of cool field brown dwarf candidates using IRAC data from the Spitzer Deep, Wide-Field Survey (SDWFS). The candidates were selected from 400,000 SDWFS sources with [4.5] <= 18.5 mag and required to have [3.6]-[4.5] >= 1.5 and [4.5] - [8.0] <= 2.0 on the Vega system. The first color requirement selects objects redder than all but a handful of presently known brown dwarfs with spectral classes later than T7, while the second eliminates 14 probable reddened AGN. Optical detection of 4 of the remaining 18 sources implies they are likely also AGN, leaving 14 brown dwarf candidates. For two of the brightest candidates (SDWFS J143524.44+335334.6 and SDWFS J143222.82+323746.5), the spectral energy distributions including near-infrared detections suggest a spectral class of ~ T8. The proper motion is < 0.25 "/yr, consistent with expectations for a luminosity inferred distance of >70 pc. The reddest brown dwarf candidate (SDWFS J143356.62+351849.2) has [3.6] - [4.5]=2.24 and H - [4.5] > 5.7, redder than any published brown dwarf in these colors, and may be the first example of the elusive Y-dwarf spectral class. Models from Burrows et al. (2003) predict larger numbers of cool brown dwarfs should be found for a Chabrier (2003) mass function. Suppressing the model [4.5] flux by a factor of two, as indicated by previous work, brings the Burrows models and observations into reasonable agreement. The recently launched Wide-field Infrared Survey Explorer (WISE) will probe a volume ~40x larger and should find hundreds of brown dwarfs cooler than T7.Comment: 13 pages, 6 figures, accepted for publication in the June 2010 issue of The Astronomical Journa

The senescent secretome drives PLVAP expression in cultured human hepatic endothelia to promote monocyte transmigration

Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP's impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease. [Abstract copyright: © 2023 The Author(s).