TLR3 and TLR4 are innate antiviral immune receptors in human microglia: Role of IRF3 in modulating antiviral and inflammatory response in the CNS

Suh, Hyeon-Sook; Zhao, Meng‐Liang; Choi, Namjong; Belbin, Thomas J.; Brosnan, Celia F.; Lee, Sunhee C.

doi:10.1016/j.virol.2009.07.001

Cited by 60 publications

(57 citation statements)

References 89 publications

(130 reference statements)

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“…However during chronic infection, TLR stimulation could induce a strong inflammatory response that would increase HIV-1 replication. This can explain the different results obtained by several research groups, showing an increase or decrease in HIV-1 replication, 14,37,38 or even transmission from DCs to CD4 + T cells, 39 after TLR stimulation when using different TLR ligands, virus strains, and cellular models (mastocytes, 16 DCs, 40 macrophages, lymphoid tissue, 41 and microglia 42 ), or animal models (transgenic mice that incorporate the HIV-1 genome). 15,43 The main goal of HAART is to block HIV-1 replication and achieve immune reconstitution in HIV-1-infected patients.…”

Section: Discussionmentioning

confidence: 98%

Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens

Hernández

Arteaga

Paul

et al. 2011

AIDS Research and Human Retroviruses

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The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.

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Section: Discussionmentioning

confidence: 98%

Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens

Hernández

Arteaga

Paul

et al. 2011

AIDS Research and Human Retroviruses

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“…For instance, an active mutant of IRF3 has been reported to exert a markedly suppressive effect on cellular HIV-1 infection, and administration of poly(I·C) potently inhibits HIV-1 replication in microglia through a pathway requiring IRF3. Nonetheless, HIV-1 itself does not activate IRF3 but, rather, decreases IRF3 protein in HIV-1-infected cells (12,37). Likewise, prion infection might disturb the activation of IRF3 even though prion is considered to be largely composed of PrP Sc .…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection

Ishibashi

Atarashi

Fuse

et al. 2012

J Virol

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Abnormal prion protein (PrP Sc ) generated from the cellular isoform of PrP (PrP C ) is assumed to be the main or sole component of the pathogen, called prion, of transmissible spongiform encephalopathies (TSE). Because PrP is a host-encoded protein, acquired immune responses are not induced in TSE. Meanwhile, activation of the innate immune system has been suggested to partially block the progression of TSE; however, the mechanism is not well understood. To further elucidate the role of the innate immune system in prion infection, we investigated the function of interferon regulatory factor 3 (IRF3), a key transcription factor of the MyD88-independent type I interferon (IFN) production pathway. We found that IRF3-deficient mice exhibited significantly earlier onset with three murine TSE strains, namely, 22L, FK-1, and murine bovine spongiform encephalopathy (mBSE), following intraperitoneal transmission, than with wild-type controls. Moreover, overexpression of IRF3 attenuated prion infection in the cell culture system, while PrP Sc was increased in prion-infected cells treated with small interfering RNAs (siRNAs) against IRF3, suggesting that IRF3 negatively regulates PrP Sc formation. Our findings provide new insight into the role of the host innate immune system in the pathogenesis of prion diseases.

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“…As previously reported, LPS induced microglial IDO expression ( Figure 4C) and iNOS was not induced in human microglia by any of the stimuli. 26,39 The expression of HO-2 (the constitutive isoform of hemeoxygenase) in microglia paralleled that of ␤-actin. Figure 5 shows representative quantitative PCR analysis of HO-1 mRNA expression in mixed neuronal glial cultures and microglial cultures.…”

Section: -Haa Induces Ho-1mentioning

confidence: 99%

“…For microglial cultures, the TLR ligands PIC (10 g/mL) and LPS (100 ng/mL) were used as stimuli. 39 For astrocytes, three different combinations of stimuli were applied (IL-1␤ alone, IL-1 and IFN-␥, or PIC) based on previously determined gene expression patterns. 22,27,34 Human astrocytes respond minimally to LPS; therefore, we excluded this stimulus for astrocytes.…”

Section: -Haa Suppresses Cytokine and Chemokine Productionmentioning

confidence: 99%

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

Krause

Suh

Tarassishin

et al. 2011

The American Journal of Pathology

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136

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Tryptophan metabolism by the kynurenine pathway (KP) is important to the pathogenesis of inflammatory, infectious, and degenerative diseases. The 3-hydroxykynurenine (3-HK) branch of the KP is activated in macrophages and microglia, leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid, which are considered neurotoxic owing to their free radical-generating and N-methyl-D-aspartic acid receptor agonist activities. We investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human fetal central nervous system cultures treated with cytokines (IL-1 with or without interferon-␥) or with Toll-like receptor ligands mimicking the proinflammatory central nervous system environment. Results were analyzed by microarray, Western blot, immunostain, enzyme-linked immunosorbent assay, and neurotoxicity assays. 3-HAA suppressed glial cytokine and chemokine expression and reduced cytokine-induced neuronal death. 3-HK also suppressed cytokineinduced neuronal death. Unexpectedly, 3-HAA was highly effective in inducing in astrocytes the expression of hemeoxygenase-1 (HO-1), an antioxidant enzyme with anti-inflammatory and cytoprotective properties. Indoleamine-2,3-dioxygenase (IDO) is an interferon (IFN)-␥-inducible, rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan metabolism generating various downstream metabolites collectively termed "kynurenines" 1 ( Figure 1). This process is compartmentalized due to cell-specific expression of the KP enzymes. For example, kynurenine monooxygenase (KMO) is expressed in macrophages and microglia, 2-4 whereas kynurenine aminotransferase II (KAT II) is present in astrocytes.5 A well-appreciated biological activity of IDO is T-cell suppression. IDO expressed in antigen-presenting cells (dendritic cells, macrophages, and microglia) can

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TLR3 and TLR4 are innate antiviral immune receptors in human microglia: Role of IRF3 in modulating antiviral and inflammatory response in the CNS

Cited by 60 publications

References 89 publications

Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens

Up-Regulation of TLR2 and TLR4 in Dendritic Cells in Response to HIV Type 1 and Coinfection with Opportunistic Pathogens

Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

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