Yi H, Yu X, Gao P, Wang Y, Baek S-H, Chen X, Kim HL, Subjeck JR, Wang X-YPattern recognition scavenger receptor SRA/CD204 down-regulates Toll-like receptor 4 signaling-dependent CD8 T-cell activation. Blood 113:5819-5828

Department of Cellular Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Blood (Impact Factor: 10.45). 05/2009; 113(23):5819-28. DOI: 10.1182/blood-2008-11-190033
Source: PubMed


Class A scavenger receptor (SRA), also known as CD204, has been shown to participate in the pathogenesis of atherosclerosis and the pattern recognition of pathogen infection. However, its role in adaptive immune responses has not been well defined. In this study, we report that the lack of SRA/CD204 promotes Toll-like receptor (TLR)4 agonist-augmented tumor-protective immunity, which is associated with enhanced activation of CD8(+) effector T cell and improved inhibition of tumor growth. Dendritic cells (DCs) deficient in SRA/CD204 display more effective immunostimulatory activities upon TLR4 engagement than those from wild-type counterparts. Silencing of SRA/CD204 by RNA interference improves the ability of DCs to prime antigen-specific CD8(+) T cells, suggesting that antigen-presenting cells, for example, DCs, play a major role in SRA/CD204-mediated immune modulation. Our findings reveal a previously unrecognized role for SRA/CD204, a non-TLR pattern recognition receptor, as a physiologic negative regulator of TLR4-mediated immune consequences, which has important clinical implications for development of TLR-targeted immunotherapeutic intervention.

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    • "This would suggest that in the airway epithelium, SRA functions, in part, as a receptor involved in the phlogistic response. It has previously been shown that in the macrophage, SRA is not involved in direct stimulation of an inflammatory response, but rather helps to negatively regulate the inflammatory response (Cotena, Gordon, & Platt, 2004; Yi et al., 2009). This is of significant importance in that the pulmonary epithelial cell is a first responder to the direct environment. "
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    ABSTRACT: Co-exposure to cigarette smoke and ethanol generates malondialdehyde and acetaldehyde, which can subsequently lead to the formation of aldehyde-adducted proteins. We have previously shown that exposure of bronchial epithelial cells to malondialdehyde-acetaldehyde (MAA) adducted protein increases protein kinase C (PKC) activity and proinflammatory cytokine release. A specific ligand to scavenger receptor A (SRA), fucoidan, blocks this effect. We hypothesized that MAA-adducted protein binds to bronchial epithelial cells via SRA. Human bronchial epithelial cells (BEAS-2B) were exposed to MAA-adducted protein (either bovine serum albumin [BSA-MAA] or surfactant protein D [SPD-MAA]) and SRA examined using confocal microscopy, fluorescent activated cell sorting (FACS), and immunoprecipitation. Differentiated mouse tracheal epithelial cells (MTEC) cultured by air-liquid interface were assayed for MAA-stimulated PKC activity and keratinocyte-derived chemokine (KC) release. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for 3–7 min and subsided by 20 min. Likewise, MAA-adducted protein co-localized to SRA from 3–7 min with a subsequent internalization of MAA by 10 min. These results were confirmed using FACS analysis and revealed a reduced mean fluorescence of SRA after 3 min. Furthermore, increased amounts of MAA-adducted protein could be detected by Western blot in immunoprecipitated SRA samples after 3 min treatment with MAA. MAA stimulated PKCε-mediated KC release in wild type, but not SRA knockout mice. These data demonstrate that aldehyde-adducted proteins in the lungs rapidly bind to SRA and internalize this receptor prior to the MAA-adducted protein stimulation of PKC-dependent inflammatory cytokine release in airway epithelium.
    Alcohol 08/2014; 48(5). DOI:10.1016/j.alcohol.2014.02.005 · 2.01 Impact Factor
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    • "Besides modified self macromolecules, a wide range of PAMPs have been identified as MSR1 ligands, including bacterial surface components (e.g., LPS) and nucleic acids (e.g., CpG DNA and double-strand RNA), apoptotic cells, and endogenous danger molecules (64). Notably, the first report about negative effects of MSR1 in DC activation and function during adaptive immunity was presented by Yi and colleagues (65), in which they demonstrated that MSR1 suppresses the ability of TLR4 stimulation to license DC to prime naive CD8 T cells, drive their expansion, and promote their cytotoxic functionality both in vitro and in vivo (65). In agreement with data from Herber et al. they showed that lack of MSR1 in hematopoietic cells promoted tumor-protective immunity in a B16-OVA mouse melanoma model. "
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    ABSTRACT: Dendritic cells (DC) are critical regulators of both activation and tolerance in the adaptive immune response. The dual nature of DC immunoregulatory function depends on their differentiation and activation status. DC found within the tumor microenvironment (TME) and tumor-draining lymph node often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. The major determinants of DC activation and the functional alterations in DC that result from integrating exogenous stimuli have been well investigated. Extensive efforts have been made to elucidate how the TME contributes to the inactivated/dysfunctional phenotype of tumor-associated DC (TADC). Although performed predominantly on in vitro DC cultures, recent evidence indicates that DC undergo required, coordinated alterations in their metabolism upon activation, and dysregulated metabolism in TADC is associated with their reduced immunostimulatory capacity. In this review, we will focus on the role of glycolysis and fatty acid metabolism in DC activation and function and discuss how these metabolic pathways may be regulated in TADC. Further, we consider the need for developing novel experimental approaches to assess metabolic choices in vivo, and the necessity for integrating metabolic regulation into the optimized development of DC for tumor vaccines and immunotherapy for cancer.
    Frontiers in Immunology 01/2014; 5:24. DOI:10.3389/fimmu.2014.00024
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    • "Also, given the fact that macrophage SRs are involved in the binding and internalization of LPS, which is part of Gram-negative bacteria [96], Thomas et al. showed that SR-A-deficient mice were more susceptible to infection with pathogens, with an impaired ability to clear bacterial infection, confirming what was shown by Suzuki et al., providing the first insight on the importance of SR-A in host defense [97, 98]. Additionally, other researchers observed that these animals showed a reduced expression of IL-1β, which is associated with a reduced mortality in response to LPS [99], showing that SR-A has a role in the macrophage activation induced by endotoxin shock [100–104]. "
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    ABSTRACT: It is widely accepted that cells serving immune functions in the brain, namely, microglia and astrocytes, are important mediators of pathological phenomena observed in Alzheimer's disease. However, it is unknown how these cells initiate the response that results in cognitive impairment and neuronal degeneration. Here, we review the participation of the immune response mediated by glial cells in Alzheimer's disease and the role played by scavenger receptors in the development of this pathology, focusing on the relevance of class A scavenger receptor (SR-A) for A β clearance and inflammatory activation of glial cell, and as a potential target for Alzheimer's disease therapy.
    Mediators of Inflammation 05/2013; 2013(8):895651. DOI:10.1155/2013/895651 · 3.24 Impact Factor
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