α1-Acid Glycoprotein Up-regulates CD163 via TLR4/CD14 Protein Pathway

Komori, Hisakazu; Watanabe, Hiroshi; Shuto, Tsuyoshi; Kodama, Azusa; Maeda, Hitoshi; Watanabe, Kenji; Kai, Hirofumi; Otagiri, Masaki; Maruyama, Toru

doi:10.1074/jbc.m112.353771

Cited by 44 publications

(25 citation statements)

References 51 publications

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“…CD163 expression is enhanced by glucocorticoids, antiinflammatory cytokines (e.g., IL-10), or growth factors that can promote monocyte-to-macrophage differentiation (e.g., macrophage CSF, M-CSF) (32, 33). The expression of CD163 is downregulated by proinflammatory cytokines (e.g., IFN-γ) and growth factors that induce monocyte to DC differentiation (e.g., granulocyte M-CSF, GM-CSF) (34).…”

Section: Discussionmentioning

confidence: 99%

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Yang¹,

Wang²,

Levine³

et al. 2016

JCI Insight

103

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Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Yang¹,

Wang²,

Levine³

et al. 2016

JCI Insight

103

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“…TLR4, which can also protect cells from oxidative stress, was unchanged by TLR3 siRNA transfection, as measured by QPCR (Fig. 2E) (Komori et al, 2012; Yi et al, 2012). …”

Section: Resultsmentioning

confidence: 94%

Toll-like receptor 3 (TLR3) protects retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism

Patel

Hackam

2013

Molecular Immunology

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Toll-like receptors (TLRs) are essential receptors of the innate immune system and are first responders for protection against bacterial and viral pathogens. Recently, several TLRs have also been implicated in regulating cell death and survival in non-pathogen injuries such as stroke and oxidative stress. Investigating the role of TLRs during central nervous system damage is an important focus of research that may reveal new mechanisms underlying the cellular response to injury and survival. Retinal pigmented epithelium (RPE) cells form an epithelial layer underneath the neural retina that maintains the function of photoreceptors and are the primary cell type affected in the retinal disease age-related macular degeneration (AMD). Predicted loss of function polymorphisms in the TLR3 gene are associated with protection from AMD but the role of TLR3 in regulating RPE survival during AMD-like injury, such as high oxidative stress, is not known. Therefore the purpose of this study is to evaluate the effect of TLR3 signaling on RPE viability during oxidative stress. We demonstrated that TLR3 activation in the presence of oxidative stress injury significantly increased RPE cell viability, in contrast to TLR3 reducing cell viability in the absence of cellular injury. Furthermore, we show signal transducer and activator of transcription 3 (STAT3) signaling as an essential mediator of TLR3-regulated protection of RPE cells. STAT3 signaling was increased by TLR3 activation and knockdown of STAT3 transcripts using siRNA abolished the protective effect of TLR3 during oxidative stress. Together, these results demonstrate a novel pro-survival role for TLR3 signaling within the RPE during injury. These findings support the concept that dysregulation of TLR3 activity may contribute to the development of AMD, suggesting that precise regulation of the TLR3 pathway during AMD-associated injury could be of therapeutic interest.

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“…Both Sn and CD163 receptors are macrophage-restricted cell surface molecules that are conserved across mammals. Among these, Sn receptor is a member of the sialic acid-binding IgG-like lectin family of proteins which contributes to sialylated pathogen uptake, antigen presentation and lymphocyte proliferation [ 25 ], while CD163 receptor is a critical for the efficient extracellular hemoglobin clearance during hemolysis [ 26 ]. Therefore, whether the knock-down of two receptors could influence the viability or compromise the cell functions of PAMs should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, whether the knock-down of two receptors could influence the viability or compromise the cell functions of PAMs should be considered. In the light of the fact that expression of the two receptors are regulated by several factors such as glucocorticoids and IL-10, and that the expression levels vary significantly under different conditions [ 15 , 26 ], we speculated that the two genes were not vital for the cell viability. This speculation was supported by an additional fact that the viability of PAM cell lines is not compromised by the loss of Sn and/or CD163 expression [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of porcine reproductive and respiratory syndrome virus infection by recombinant adenovirus- and/or exosome-delivered the artificial microRNAs targeting sialoadhesin and CD163 receptors

Zhu

Song

Zhang

et al. 2014

Virol J

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BackgroundThe current vaccines failed to provide substantial protection against porcine reproductive and respiratory syndrome (PRRS) and the new vaccine development faces great challenges. Sialoadhesin (Sn) and CD163 are the two key receptors for PRRS virus (PRRSV) infection of porcine alveolar macrophages (PAMs), but the artificial microRNA (amiRNA) strategy targeting two viral receptors has not been described.MethodsThe candidate miRNAs targeting Sn or CD163 receptor were predicted using a web-based miRNA design tool and validated by transfection of cells with each amiRNA expression vector plus the reporter vector. The amiRNA-expressing recombinant adenoviruses (rAds) were generated using AdEasy Adenoviral Vector System. The rAd transduction efficiencies for pig cells were measured by flow cytometry and fluorescent microscopy. The expression and exosome-mediated secretion of amiRNAs were detected by RT-PCR. The knock-down of Sn or CD163 receptor by rAd- and/or exosome-delivered amiRNA was detected by quantitative RT-PCR and flow cytometry. The additive anti-PRRSV effect between the two amiRNAs was detected by quantitative RT-PCR and viral titration.ResultsAll 18 amiRNAs validated were effective against Sn or CD163 receptor mRNA expression. Two rAds expressing Sn- or CD163-targeted amiRNA were generated for further study. The maximal rAd transduction efficiency was 62% for PAMs at MOI 800 or 100% for PK-15 cells at MOI 100. The sequence-specific amiRNAs were expressed efficiently in and secreted from the rAd-transduced cells via exosomes. The expression of Sn and CD163 receptors was inhibited significantly by rAd transduction and/or amiRNA-containing exosome treatment at mRNA and protein levels. Both PRRSV ORF7 copy number and viral titer were reduced significantly by transduction of PAMs with the two rAds and/or by treatment with the two amiRNA-containing exosomes. The additive anti-PRRSV effect between the two amiRNAs was relatively long-lasting (96 h) and effective against three different viral strains.ConclusionThese results suggested that Sn- and CD163-targeted amiRNAs had an additive anti-PRRSV effect against different viral strains. Our findings provide new evidence supporting the hypothesis that exosomes can also serve as an efficient small RNA transfer vehicle for pig cells.

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α1-Acid Glycoprotein Up-regulates CD163 via TLR4/CD14 Protein Pathway

Cited by 44 publications

References 51 publications

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Toll-like receptor 3 (TLR3) protects retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism

Inhibition of porcine reproductive and respiratory syndrome virus infection by recombinant adenovirus- and/or exosome-delivered the artificial microRNAs targeting sialoadhesin and CD163 receptors

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