Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor‐A and scavenger receptor expressed by endothelial cells‐I

Facciponte, John G.; Wang, Xiangyang; Subjeck, John R.

doi:10.1002/eji.200737127

Cited by 69 publications

(88 citation statements)

References 54 publications

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“…Among them, scavenger receptor SRA/CD204 has been described as a receptor for high molecular weight HSPs such as HSP110. 22,42 Although in our experimental setting this receptor was not involved, other authors have shown that it mediates an inhibitory signal in dendritic cells upon HSP110 stimulation, thus supporting our hypothesis that extracellular HSP110 is deleterious to optimal immune responses. Thus, as suggested by W. Van Eden for other HSP family members, HSP110 should therefore not be considered a DAMP (accordingly to the concept of "danger" introduced by P. Matzinger) but rather as a "DAMPer" of the immune system.…”

Section: E1170264-6supporting

confidence: 87%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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HSP110 is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps the cells to survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently showed that colorectal cancer (CRC) patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110 inactivating mutation (HSP110DE9). In this work, we have used patients' biopsies and human CRC cells grown in vitro and in vivo (xenografts) to demonstrate that (1) HSP110 is secreted by CRC cells and that the amount of this extracellular HSP110 is strongly decreased by the expression of the mutant HSP110DE9, (2) Supernatants from CRC cells overexpressing HSP110 or purified recombinant human HSP110 (LPS-free) affect macrophage differentiation/polarization by favoring a pro-tumor, anti-inflammatory profile, (3) Conversely, inhibition of HSP110 (expression of siRNA, HSP110DE9 or immunodepletion) induced the formation of macrophages with a cytotoxic, pro-inflammatory profile. (4) Finally, this effect of extracellular HSP110 on macrophages seems to implicate TLR4. These results together with the fact that colorectal tumor biopsies with HSP110 high were infiltrated with macrophages with a pro-tumoral profile while those with HSP110 low were infiltrated with macrophages with a cytotoxic profile, suggest that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes associated with HSP110 expression.

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Section: E1170264-6supporting

confidence: 87%

Extracellular HSP110 skews macrophage polarization in colorectal cancer

et al. 2016

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“…Finally, to date, SR-A and SREC-I have been identified as receptors for ORP150 expressed on APCs (20). However, whether SR-A or SREC-I is responsible for the efficient cross-presentation by DCs remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…It is thought that HSPs bind to receptors on APCs, resulting in secretion of proinflammatory cytokines and maturation and activation of dendritic cells (DCs). To date, CD91 (14 -16), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) (17), CD40 (18), scavenger receptor type A (SR-A) (19,20), and scavenger receptor expressed by endothelial cells-I (SREC-I) (20,21) have been demonstrated to be receptors for several kinds of HSPs expressed on APCs.…”

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confidence: 99%

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Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes

Kutomi

Tamura²,

Okuya

et al. 2009

The Journal of Immunology

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Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit intriguing, efficient CTL responses by cross-presentation via an as yet entirely unknown mechanism. Oxygen-regulated protein 150 (ORP150), also known as grp170, is an endoplasmic reticulum-resident HSP and is up-regulated by hypoxia. It has been demonstrated that ORP150 binds tumor-associated Ag peptides within cancer cells. Immunization with an ORP150-tumor Ag complex has been shown to generate tumor-specific CTLs. Most recently, it has been shown that exogenous ORP150 induces cross-presentation of a chaperoned Ag, thereby stimulating Ag-specific CTLs. However, the mechanism underlying this efficient cross-presentation is still unsolved. In this study, we show that the ORP150-precursor peptide complex can elicit CTL response through cross-presentation as well as the CD4+ T cell response by dendritic cells. Furthermore, we observed that the internalized ORP150-peptide complex, but not OVA protein, which was not cross-presented, was sorted to the Rab5+, EEA1+ static early endosome, followed by translocation to a recycling endosome, where the ORP150-chaperoned peptide was processed and bound to MHC class I molecules. Moreover, we observed that immunization of mice with ORP150-peptide complexes elicited strong peptide-specific CTLs and antitumor effects in vivo. Our data indicate that targeting of the Ag to a “static” early endosme by ORP150 is required for the efficient cross-presentation.

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“…Higher Hsp110 has been shown to act as a "danger signal" to DCs (55), and Hsp105/Hsp110-pulsed BMDCs induce the regression of intestinal adenomas in vivo (56). 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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Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor‐A and scavenger receptor expressed by endothelial cells‐I

Cited by 69 publications

References 54 publications

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Extracellular HSP110 skews macrophage polarization in colorectal cancer

Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes

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

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