Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation

Ouyang, Xinshou; Negishi, Hideo; Takeda, Ryoji; Fujita, Yasuyuki; Taniguchi, Tadatsugu; Honda, Kenya

doi:10.1016/j.bbrc.2007.01.090

Cited by 103 publications

(70 citation statements)

References 18 publications

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“…TLR4 signaling is controlled by MyD88-or TRIF-dependent downstream effectors, the signals of which converge for TRAF6 activation and NF-kB nuclear translocation (56). IRAK1 and IRF5 are primarily known to be involved downstream of MyD88 (52), but IRF5 is also involved in TRIF-mediated responses (57). In acid aspiration lung injury, TLR4/TRIF/TRAF6 signaling in lung macrophages was shown to determine the susceptibility to ARDS in vivo (12,33).…”

Section: Discussionmentioning

confidence: 99%

“…In acid aspiration lung injury, TLR4/TRIF/TRAF6 signaling in lung macrophages was shown to determine the susceptibility to ARDS in vivo (12,33). Both TRAF6 and IRF5 lead to NF-kB activation, but IRF5 is also an important regulator of iNOS and IL-12b expression and, thus, M1 polarization (23,52,(57)(58)(59)(60). We found that WT macrophages upregulate TRAF6 and IRF5 gene expression in line with their M1 phenotype, whereas Akt2-deficient macrophages, having an M2 phenotype, exhibit reduced levels of these factors both at baseline and upon acid injury.…”

Section: Discussionmentioning

confidence: 99%

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Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

147

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

147

106

View full text Add to dashboard Cite

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“…However, we observed a consistent and significant decrease in LPS-induced IL-12p70 and IL-12p40 secretion when DCs were treated with CO. Generation of the active IL12p70 required the expression of both IL-12p40 and IL-12p35 subunits. TLR3 and TLR 4-induced IL-12p35 (55) and IL-12p40 (56) expression have been shown to be dependent on IRF-3 phosphorylation. In mouse macrophages, HO-1 and CO have been described to inhibit the LPS-induced phosphorylation of IRF-3, whereas TLR3-induced IRF3 activation was inhibited by HO-1 but not by CO (57).…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

Remy

Blancou

Tesson

et al. 2009

The Journal of Immunology

114

131

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Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe 2؉ , and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocytederived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. H eme oxygenases are the rate-limiting enzymes in the catabolism of heme, yielding equimolar amounts or carbon monoxide (CO), 5 free iron, and biliverdin (BV) (1), which is subsequently reduced into bilirubin (BL). Heme oxygenase 1 (HO-1), the inducible form of heme oxygenases, has protective effects in a variety of experimental inflammatory models (reviewed in Ref.2). The physiological importance of HO-1 has been demonstrated in both mice and humans, where HO-1 deficiency resulted in a progressive and chronic inflammation and a reduced cellular resistance to oxidative stress (3-5). Induction of HO-1 expression by pharmacological activators or gene transfer have therapeutic effects in a variety of conditions or disorders involving inflammation and immune responses, including organ transplantation and autoimmunity (6 -12). In several models, CO mimics the effects of HO-1 (reviewed in Ref. 13), indicating that HO-1 acts via the generation of CO. However, other end products of HO-1 activity, such as BV (14), free iron depletion by increased H chain ferritin expression (15), or cellular efflux pumps (16), or heme depletion (17) can also mediate the effects of HO-1.Dendritic cells (DCs) play a major role in the initiation and regulation of the immune response. They have distinct stages of cell development, activation, and maturation and have the potential to induce both immunity and tolerance (reviewed in Ref. 18). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues continuously capture innocuous and cell-associated self-Ags and migrate to draining lymph nodes where they can induce tolerance (19). In the presence of danger and TLR signals, DCs mature, acquiring the ability to stimulate differentiation of naive T cells into effector cells. In certain conditions, phenotypically mature DCs have tolerogenic functions (18).We previously showed that human and rat iDCs express HO-1, that this expression is restricted to certain DC populations, and that HO-1 expression drastically decreases upon DC maturation (20). We and others have demonstrated that overexpression of HO-1 in DCs inhibits their LPS-induced maturation and proinflammatory functions (20,21), and it has been recently...

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“…Four TLRs (TLR2-5) are expressed in both normal ovary epithelial cells and ovarian cancer cell lines (Zhou et al, 2009). The significance of the expression of multiple TLRs in a wide range of cancer cells is not fully understood; however, simultaneous activation of multiple TLR types might be able to enhance the biological response, as in the case of synergistic effects by combined TLR ligation reported for cytokine production in DCs (Whitmore et al, 2004;Roelofs et al, 2005;Warger et al, 2006;Gautier et al, 2005;Theiner et al, 2007;Zhu et al, 2008;Krummen et al, 2010) and macrophages (Sato et al, 2000;Ouyang et al, 2007). It is possible that tumor cells express multiple TLRs to recognize various DAMPs in their microenvironment, and thereby enhance the biological process triggered by TLR activation to produce favorable conditions for growth and survival.…”

Section: Positive Effects Of Tlrs In Cancer Developmentmentioning

confidence: 99%