Phosphoinositide-Mediated Adaptor Recruitment Controls Toll-like Receptor Signaling

Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell (Impact Factor: 32.24). 07/2006; 125(5):943-55. DOI: 10.1016/j.cell.2006.03.047
Source: PubMed


Toll-like receptors (TLRs) play a critical role in the immune system as sensors of microbial infection. Signaling downstream from TLRs is initiated by the recruitment of adaptor proteins, including MyD88 and TIRAP. These adaptors play essential roles in TLR signaling, but the mechanism of their function is currently unknown. Here we demonstrate that TIRAP and MyD88 have distinct functions and describe a mechanism of recruitment of TIRAP and MyD88 to TLR4. We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. These results establish that phosphoinositide-mediated adaptor recruitment initiates a specific signal-transduction pathway.

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    • "LPS binds to TLR-4 on the cell membrane and induces NF-κB transcription, mainly through the MyD88 signaling pathway. NF-κB is a transcriptional factor that controls the expression of numerous genes involved in inflammation, which leads to a release of the critical inflammatory molecules, conducting the appropriate immune response (Kagan and Medzhitov, 2006; Peng et al., 2012). Taken together, data presented here from in vivo and in vitro studies show the mechanisms of the antiinflammatory actions of R. officinalis aqueous extract in early phases of inflammation. "
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    ABSTRACT: Rosmarinus officinalis L. phenolic compounds have attracted considerable attention because of their antioxidant and antimicrobial properties, including its ability to treat inflammatory disorders. In this work, we investigated the in vivo and in vitro effects of R. officinalis aqueous extract on neutrophil trafficking from the blood into an inflamed tissue, on cell-derived secretion of chemical mediators, and on oxidative stress. Anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Wistar rats orally treated with the R. officinalis extract (100, 200, or 400 mg/kg). The leukocyte influx (optical microscopy), secretion of chemical mediators (prostaglandin E2 (PGE2), TNF-α, interleukin 6 (IL-6), leukotriene B4 (LTB4), and cytokine-induced neutrophil chemoattractant 1 by enzyme-linked immunosorbent assay), and the anti-oxidative profile (super oxide dismutase (SOD), glutathione peroxidase, and thiobarbituric acid reactive substance (TBARS) spectrophotometry) were quantified in the inflamed exudate. N-Formyl-methionine-leucine-phenylalanine-induced chemotaxis, lipopolysaccharide-induced NO2 (-) production (Greiss reaction), and adhesion molecule expression (flow cytometry) were in vitro quantified using oyster glycogen recruited peritoneal neutrophils previous treated with the extract (1, 10, or 100 µg/mL). Animals orally treated with phosphate-buffered saline and neutrophils incubated with Hank's balanced salt solution were used as control. R. officinalis extract oral treatment caused a dose-dependent reduction in the neutrophil migration as well as decreased SOD, TBARS, LTB4, PGE2, IL-6, and TNF-α levels in the inflamed exudate. In vitro treatment with R. officinalis decreased neutrophil chemotaxis, NO2 (-) production, and shedding of L-selectin and β2 integrin expressions. Results here presented show that R. officinalis aqueous extract displays important in vivo and in vitro anti-inflammatory actions by blocking pathways of neutrophil migration and secretion, suggesting its therapeutic application to acute inflammatory reactions. Copyright © 2014 John Wiley & Sons, Ltd.
    Phytotherapy Research 10/2014; 29(1). DOI:10.1002/ptr.5238 · 2.66 Impact Factor
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    • "The lipid-binding domain of TIRAP binds to PI(4,5)P2 at the plasma membrane and to PI(3)P on endosomes, which mediates the formation of functional TLR4 and TLR9 signaling complexes at their respective sites. Thus, TIRAP associates with both cell surface and endosomal TLRs by binding to different lipids (38). However, a high concentration of TLR9 agonists activates cells in the absence of TIRAP, suggesting that TIRAP is required for TLR9 signaling in natural situations such as HSV-1 infection (39). "
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    ABSTRACT: Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
    Frontiers in Immunology 09/2014; 5:461. DOI:10.3389/fimmu.2014.00461
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    • "However, the observed M3G-related neuronal signaling events are rapid and may be independent of signal transcription factors. Alternatively, the assembly of TLR adapter signaling proteins and activation of phospholipids in neurons may only require activation of a signal-transduction pathway leading to the observed increase in NaV current [50]. Additional studies are also underway to determine the degree to which hormonal regulation of neuronal TLR4 responses serve to influence neuropathic pain states alone or in combination with opioids [48], [51]. "
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    ABSTRACT: Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.
    PLoS ONE 09/2014; 9(9):e107399. DOI:10.1371/journal.pone.0107399 · 3.23 Impact Factor
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