Impaired Toll-like Receptor 9 Expression in Alveolar Macrophages with No Sensitivity to CpG DNA

Suzuki, Kazutoshi; Suda, Takafumi; Naito, Tateaki; Ide, Kyotaro; Chida, Kingo; Nakamura, Hirotoshi

doi:10.1164/rccm.200408-1078oc

Cited by 67 publications

(52 citation statements)

References 41 publications

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“…In line with the current results, stimulation with LPS in vitro has been shown to reduce TLR4 mRNA and increase TLR2 mRNA levels in murine alveolar macrophages [7] and to enhance TLR2 mRNA and protein levels in human alveolar macrophages [6]. TLR9 mRNA has not been detected in murine alveolar macrophages [18]. However, in contrast with the current human in vivo study, LPS did not influence the mRNA levels of TLR1, CD14 or MD-2 in murine alveolar macrophages in vitro [7].…”

Section: Discussionsupporting

confidence: 90%

Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin

Maris¹,

Dessing²,

Vos³

et al. 2006

Eur Respir J

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Toll-like receptors (TLRs) are pattern-recognition receptors that have been implicated in the initiation of innate immune responses upon the first encounter with invading pathogens. The airways are frequently exposed to various types of lipopolysaccharide (LPS) from the environment or from pathogens. The current study was designed to determine the effect of LPS on TLR gene expression in human alveolar macrophages in vivo.In total, 16 healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 mg LPS or normal saline (n58 per group). Measurements were performed in alveolar macrophages purified from bronchoalveolar lavage fluid obtained 6 h post-challenge.Inhalation of LPS by healthy human volunteers resulted in enhanced alveolar macrophage expression of mRNAs encoding TLRs 1, 2, 7, 8 and CD14, and reduced expression of mRNAs encoding TLR4 and lymphocyte antigen 96.In conclusion, lipopolysaccharide differentially influences the toll-like receptor mRNA expression profile in human alveolar macrophages in vivo.

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Section: Discussionsupporting

confidence: 90%

Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin

Maris¹,

Dessing²,

Vos³

et al. 2006

Eur Respir J

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“…This results in impaired T cell stimulation of both CD4 ϩ and CD8 ϩ T cells and contributes to the reduced pulmonary inflammatory response to inhaled Ags. The expression of TLR9 and the response of lung DC to CpG have been previously demonstrated by others (34,35). In contrast to studies using splenic or peripheral lymph node DC after systemic CpG injection (26), CpG-induced maturation of lung DC did not down-regulate their constitutive MHC class II-mediated Ag presentation.…”

Section: Discussionmentioning

confidence: 64%

Impaired Lung Dendritic Cell Migration and T Cell Stimulation Induced by Immunostimulatory Oligonucleotides Contribute to Reduced Allergic Airway Inflammation

Constabel

Stankov

Hartwig

et al. 2009

The Journal of Immunology

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CpG-containing oligonucleotides (CpG) have been shown to reduce key features of allergic airway inflammation in mouse models. Given the inhibitory effects of CpG treatment on Ag presentation of subsequently encountered Ags via MHC class I and II molecules by dendritic cells (DC), we hypothesized that intranasal CpG treatment would lead to reduced Ag-specific T cell stimulation in the lung-draining lymph nodes, thereby reducing the inflammatory response in sensitized mice. Intranasal CpG administration led to phenotypic maturation of lung and mediastinal lymph node DC as determined by expression of MHC class II, CD80, and CD86. This was accompanied by a significant reduction in the proliferation of adoptively transferred Ag-specific CD4+ and CD8+ T cells in mediastinal lymph nodes, when CpG was given before inhalative OVA challenges. DC obtained from mediastinal lymph nodes of CpG-treated mice before OVA inhalation led to reduced T cell stimulation via MHC class I and II molecules. In addition, CpG diminished airway eosinophilia and pulmonary infiltration after sensitization or following adoptive transfer of Ag-specific Th2 cells. These results were explained by reduced CCL21 expression and inhibition of lung DC migration following CpG administration, which could be restored by transfer of bone marrow-derived DC, because CpG had no major impact on the constitutive MHC class II Ag presentation of protein-derived Ag by lung tissue-derived DC. We conclude that CpG treatment can effectively impair the DC-mediated Ag transport from the lungs to the lymph nodes, resulting in reduced T cell activation and blunted airway inflammation.

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“…In humans, TLR9 expression in mononuclear blood cells and lymphoid organs is restricted to B cells and plasmacytoid DCs (pDCs), according to a consensus of the best quality data (18)(19)(20). In mice, however, TLR9 expression and ISS responsiveness have been demonstrated in macrophages, myeloid DCs (mDCs), and activated T cells in addition to pDCs and B cells (21)(22)(23)(24). Expression of TLR9 on more diverse cell types may result in additional proinflammatory mediators being released in rodents in response to ISS compared with humans and nonhuman primates (14,23).…”

Section: Introductionmentioning

confidence: 99%

CpG-containing immunostimulatory DNA sequences elicit TNF-α–dependent toxicity in rodents but not in humans

Campbell¹,

Cho²,

Foster³

et al. 2009

J. Clin. Invest.

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CpG-containing immunostimulatory DNA sequences (ISS), which signal through TLR9, are being developed as a therapy for allergic indications and have proven to be safe and well tolerated in humans when administrated via the pulmonary route. In contrast, ISS inhalation has unexplained toxicity in rodents, which express TLR9 in monocyte/macrophage lineage cells as well as in plasmacytoid DCs (pDCs) and B cells, the principal TLR9-expressing cells in humans. We therefore investigated the mechanisms underlying this rodent-specific toxicity and its implications for humans. Mice responded to intranasally administered 1018 ISS, a representative B class ISS, with strictly TLR9-dependent toxicity, including lung inflammation and weight loss, that was fully reversible and pDC and B cell independent. Knockout mouse experiments demonstrated that ISSinduced toxicity was critically dependent on TNF-α, with IFN-α required for TNF-α induction. In contrast, human PBMCs, human alveolar macrophages, and airway-derived cells from Ascaris suum-allergic cynomolgus monkeys did not produce appreciable TNF-α in vitro in response to ISS stimulation. Moreover, sputum of allergic humans exposed to inhaled ISS demonstrated induction of IFN-inducible genes but minimal TNF-α induction. These data demonstrate that ISS induce rodent-specific TNF-α-dependent toxicity that is absent in humans and reflective of differential TLR9 expression patterns in rodents versus humans.

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Impaired Toll-like Receptor 9 Expression in Alveolar Macrophages with No Sensitivity to CpG DNA

Cited by 67 publications

References 41 publications

Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin

Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin

Impaired Lung Dendritic Cell Migration and T Cell Stimulation Induced by Immunostimulatory Oligonucleotides Contribute to Reduced Allergic Airway Inflammation

CpG-containing immunostimulatory DNA sequences elicit TNF-α–dependent toxicity in rodents but not in humans

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