Scavenger Receptor-A Negatively Regulates Antitumor Immunity

Wang, Xiangyang; Facciponte, John G.; Chen, Xing; Subjeck, John R.; Repasky, Elizabeth A.

doi:10.1158/0008-5472.can-06-3138

Cited by 72 publications

(93 citation statements)

References 39 publications

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“…For example, it has been shown that scavenger receptor A family members negatively regulate immune activity triggered by tumors, fungal pathogens, and apoptotic cells (11,42,43). In our studies, we have shown that dual engagement of SR-B1 and TLR9 by CpG negatively regulates the production of pro-inflammatory mediators such as IL-6 and IL-10.…”

Section: Discussionmentioning

confidence: 52%

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

Zhu¹,

Liu²,

Treml

et al. 2009

Journal of Biological Chemistry

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It is well established that CpG promotes pro-inflammatory cytokine and antibody production by B cells via the Toll-like receptor 9 (TLR9)-dependent pathway. However, scavenger receptors (SRs) are also capable of binding such pathogen-derived molecules, yet their contribution to CpG-induced signaling events has not yet been evaluated. Here we identified a novel TLR9-independent mechanism of CpG-induced signaling and immune function that is mediated by the scavenger B1 receptor (SR-B1). Specifically, we show that CpG/SR-B1 triggers calcium entry into primary B lymphocytes via phospholipase C␥-1-mediated activation of TRPC3 channels and also B cell adhesion to vascular cell adhesion molecule-1. CpG-induced calcium signals and vascular cell adhesion molecule-1 adhesion are TLR9-independent and are mediated exclusively by SR-B1. Although proinflammatory cytokine and Ig production induced by CpG require TLR9 expression, we also found that SR-B1 negatively regulates TLR9-dependent production of interleukin-6, interleukin-10, and IgM. Thus, our results provide a novel perspective on the complexity of CpG signaling within B cells by demonstrating that SR-B1 is an alternative pathway for nucleic acid-induced signaling that provides feedback inhibition on specific TLR9-dependent responses of B cells. Consequently, these results have wide implications for understanding the mechanisms regulating immune tolerance to nucleic acids and pathogen-associated molecules.Stimulus-induced dynamic changes in the concentration of cytoplasmic calcium are primary determinants of the activation, immunological function, and developmental fate of lymphocytes. Calcium signaling through the B cell antigen receptor (BCR) 2 complex is initiated by the activation of proximal tyrosine kinases Lyn and Syk, which phosphorylate the adaptor BLNK to facilitate its association with and activation of PLC␥-2. PLC␥2 hydrolyzes phosphatidylinositol 4,5-bisphosphate into diacylglycerol and 1,4,5-inositol trisphosphate (IP 3 ) (for review see Ref. 1), which activates IP 3 receptor/channels that mediate Ca 2ϩ release from endoplasmic reticulum into the cytosol (2) (for review see Refs. 3, 4). Ca 2ϩ release from endoplasmic reticulum stores and the resulting depletion of Ca 2ϩ(not an increase in cytoplasmic [Ca 2ϩ ]) are the central and prerequisite events required to activate plasma membrane "storeoperated" calcium release-activated calcium (CRAC) channels.CRAC channels are responsible for antigen receptor-triggered calcium entry; however, a growing body of evidence suggests that CRAC channels do not underlie all the diverse calcium-regulated responses of lymphocytes, particularly those triggered by innate stimuli. For example, we previously identified several calcium-permeant non-selective cation channels (NSCCs) that are uniquely activated by distinct arachidonic acid-derived (eicosanoid) inflammatory mediators and by mechanical stimuli (5-7). Thus, multiple calcium-permeant channels with distinct activation mechanisms may underlie stimulus-specific calciu...

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Section: Discussionmentioning

confidence: 52%

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

Zhu¹,

Liu²,

Treml

et al. 2009

Journal of Biological Chemistry

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“…Recently, it was reported that some member of the "Hsp70-superfamily" binds to scavenger receptors extracellularly (57). However, scavenger receptors negatively regulate antitumor immunity (58).…”

Section: Discussionmentioning

confidence: 99%

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

Srivastava

Varalakshmi

Khar

2008

The Journal of Immunology

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Tumor recognition and killing, the uptake of released immunogenic substrate, and the generation of immunity are crucial aspects of dendritic cell (DC)-mediated antitumor immune response. In the context of direct tumoricidal activity, we have recently shown NK cell receptor protein-2 (NKR-P2)/NK group 2 member D (NKG2D) as a potent activation receptor on rat DCs. The activation of DCs with agonistic anti-NKR-P2 mAb, the binding of soluble NKR-P2 to the AK-5 tumor, and DC maturation with fixed AK-5 cells led us to identify a putative NKR-P2 ligand on the AK-5 cell surface. In this study we have shown that the AK-5 tumor-derived ischemia-responsive protein-94 (Irp94, a 110 kDa Hsp family member) acts as a functional ligand for NKR-P2 on DCs and enhances Irp94-NKR-P2 interaction-dependent tumor cell apoptosis via NO. Surface expression of Irp94 was also found on tumors of diverse origin in addition to AK-5. Furthermore, the Th1-polarizing cytokine IL-12, produced from Irp94-ligated BMDCs, augments NK cell cytotoxicity. Irp94-NKR-P2 interaction drives the maturation of BMDCs by up-regulating MHC class II, CD86, and CD1a and also induces autologous T cell proliferation, which displays a crucial state of DCs for adaptive antitumor immune response. These functional properties of Irp94 reside in the COOH terminus subdomain but not in the NH2 terminus ATPase domain of Irp94. We also show the involvement of PI3K, ERK, protein kinase C, phosphatases, and NF-κB translocation as downstream mediators of DCs activation upon NKR-P2 ligation with Irp94. Our studies demonstrate for the first time a novel role of a 110-kDa heat shock protein (Irp94) as a ligand for NKR-P2 on DCs, which in turn executes both innate and adaptive immunity.

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“…For scavenger receptors alone, heat shock proteins can interact with family members SRA1, SREC-1, LOX-1 and FEEL-1 ). In addition, heat shock protein binding to SRA1 is immunosuppressive, whereas LOX-1 mediates Hsp70 immunogenicity and antigen crosspresentation (Wang et al 2007). Detailed studies of each receptor subtype and its interaction with others are essential in order to determine the sequelae of cellular interactions with heat shock proteins.…”

Section: The Issue Of Heat Shock Protein Receptorsmentioning

confidence: 99%

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

Henderson

Calderwood

Coates

et al. 2010

Cell Stress and Chaperones

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In recent years, it has been hypothesised that a new signalling system may exist in vertebrates in which secreted molecular chaperones form a dynamic continuum between the cellular stress response and corresponding homeostatic physiological mechanisms. This hypothesis seems to be supported by the finding that many molecular chaperones are released from cells and act as extracellular signals for a range of cells. However, this nascent field of biological research seems to suffer from an excessive criticism that the biological activities of molecular chaperones are due to undefined components of the microbial expression hosts used to generate recombinant versions of these proteins. In this article, a number of the proponents of the cell signalling actions of molecular chaperones take this criticism head-on. They show that sufficient evidence exists to support fully the hypothesis that molecular chaperones have cell-cell signalling actions that are likely to be part of the homeostatic mechanism of the vertebrate.

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Scavenger Receptor-A Negatively Regulates Antitumor Immunity

Cited by 72 publications

References 39 publications

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

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