Macrophage tolerance induced by stimulation with Toll-like receptor 7/8 ligands

Tsukada, Kunihisa; Kitazawa, Takatoshi; Fukushima, Atsuhito; Okugawa, Shu; Yanagimoto, Shintaro; Tatsuno, Keita; Koike, Kazuhiko; Nagase, Hiroyuki; Hirai, Koichi; Ota, Yasuo

doi:10.1016/j.imlet.2007.05.001

Cited by 15 publications

(21 citation statements)

References 22 publications

(47 reference statements)

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“…In addition, decreased signaling through the adapter molecule IRAK-1 has been shown to mediate TLR7 tolerance in murine macrophages (15,19). We found that IRAK-1 was depleted within minutes of R848 stimulation in plasmacytoid DCs and was maintained at low levels for at least 24 hours.…”

Section: Discussionmentioning

confidence: 62%

“…Indeed, TLR7 tolerance has recently been shown to limit the development of autoimmunity (14), but whether it plays a role in the outcome of cancer immunotherapy with TLR7 agonists is not known. Furthermore, although TLR7 tolerance has been described in vitro in macrophages (13,15), it is not known whether this effect occurs in DCs, which are central to cancer immunotherapy. Here we investigated TLR7 tolerance both in vivo and in vitro and examined the consequences on DCs, in particular with respect to the induction of the anticancer cytokines interleukin (IL)-12p70 and IFN-a.…”

Section: Introductionmentioning

confidence: 99%

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Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

et al. 2011

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Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-a production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy. Cancer Res; 71(15); 5123-33. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

et al. 2011

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“…Cells were stimulated with the indicated concentrations of the following TLR agonists: 1000 ng/ml LPS (TLR4 ligand) from Escherichia coli, serotype O111:B4; palmitoyl-3-cysteine-serine-lysine-4 (TLR2/TLR1 ligand); PGN (TLR2 ligand); Pam2 (TLR2 ligand); imidazoquinoline compounds, such as R848 (TLR7/8 agonist), or imiquimod (TLR7 agonist); CpG-ODN (TLR9 ligand); poly I:C (TLR3 ligand); and 300 ng/ml recombinant Flag (TLR5 ligand). All of these TLR ligands were ultrapure, obtained from InvivoGen (San Diego, CA, USA), and reconstituted in endotoxin-free water, which was used at previously reported concentrations [16,26]. THP-1 monocytic cells were differentiated into macrophages (THP-1 macrophages), following the methods described previously [27,28], and can be considered as a suitable, noninvasive tool for macrophage-associated studies.…”

Section: Cell Culture and Innate Immune Ligand Stimulationmentioning

confidence: 99%

“…In vitro induction of homologous and heterologous TLR signaling tolerance LPS-or R848-induced tolerance and cross-tolerance using monocytes and/or macrophages were adapted from methods described previously with minor modifications [16,23,26,[30][31][32]. In the TLR signaling tolerance assays, PMAtreated, adherent THP-1 macrophages were treated with a low dose of LPS (50 ng/ml) for 18 h to prime the cells.…”

Section: Cell Culture and Innate Immune Ligand Stimulationmentioning

confidence: 99%

TLR4, TLR7/8 agonist-induced miR-146a promotes macrophage tolerance to MyD88-dependent TLR agonists

Nahid

Benso

Shin

et al. 2016

Journal of Leukocyte Biology

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TLRs facilitate the recognition of pathogens by immune cells and the initiation of the immune response, leading to the production of proinflammatory cytokines and chemokines. Production of proinflammatory mediators by innate immune cells, such as macrophages, is tightly regulated to facilitate pathogen clearance while limiting an adverse impact on host tissue. Exposure of innate immune cells to TLR ligands induces a state of temporary refractoriness to a subsequent exposure of a TLR ligand, a phenomenon referred to as “tolerance.” This study sought to evaluate the mechanistic regulation of TLR4 and TLR7/8 ligand-induced tolerance to other TLRs by microRNA-146a. With the use of THP-1 macrophages, as well as human classic and alternative macrophages, we demonstrate that priming with a TLR4 agonist (LPS) or a TLR7/8 agonist (R848) induces homologous and heterologous tolerance to various TLR ligands in macrophages, leading to the impaired production of cytokines and chemokines. We also demonstrate that overexpression of microRNA-146a is sufficient to mimic LPS or R848-induced hyporesponsiveness. Conversely, inhibition of microRNA-146a activity leads to LPS- or R848-induced TLR hyper-responsiveness in TLR signaling tolerance. Furthermore, we demonstrate that microRNA-146a dampens cytokine production following a primary stimulus with MyD88-dependent but not MyD88-independent TLR pathways. Collectively, these data provide comprehensive evidence of the central role of microRNA-146a in TLR signaling tolerance to plasma membrane, as well as endosomal TLR ligands in human macrophages.

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“…In a murine model of SLE, the genetic loss of TLR7 ameliorated disease, decreased lymphocyte activation and reduced serum IgG (16). These findings prompted us to hypothesize that repeated stimulation with a synthetic TLR7 agonist, at well tolerated low doses (10,17,18), might also restrain autoimmune inflammation.…”

mentioning

confidence: 99%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.arthritis ͉ encephalomyelitis ͉ synthetic agonist

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Macrophage tolerance induced by stimulation with Toll-like receptor 7/8 ligands

Cited by 15 publications

References 22 publications

Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance

TLR4, TLR7/8 agonist-induced miR-146a promotes macrophage tolerance to MyD88-dependent TLR agonists

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

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