Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373-384

Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Nature Immunology (Impact Factor: 20). 05/2010; 11(5):373-84. DOI: 10.1038/ni.1863
Source: PubMed


The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

  • Source
    • "However, no studies have identified reliable and effective agents against mastitis. The structure of TLR4 consists of a leucine-rich repeat-containing extracellular domain, which is a membranespanning helix and cytosolic TIR domain [17] [18]. The TIR domain consists of five-stranded parallel β-strands that are surrounded by five helixes [19] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: [TRIAP]-derived decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRIAP-derived decoy peptide (TR6) containing, the N-terminal portion of the third helical region of the [TIRAP] TIR domain (sequence "N"-RQIKIWFQNRRMKWK and -KPGFLRDPWCKYQML-"C"). We evaluated the effects of TR6 on lipopolysaccharide-induced mastitis in mice. In vivo, the mastitis model was induced by LPS administration for 24 h, and TR6 treatment was initiated 1 h before or after induction of LPS. In vitro, primary mouse mammary epithelial cells and neutrophils were used to investigate the effects of TR6 on LPS-induced inflammatory responses. The results showed that TR6 significantly inhibited mammary gland hisopathologic changes, MPO activity, and LPS-induced production of TNF-α, IL-1β and IL-6. In vitro, TR6 significantly inhibited LPS-induced TNF-α and IL-6 production and phosphorylation of NF-κB and MAPKs. In conclusion, this study demonstrated that the anti-inflammatory effect of TR6 against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB and MAPK signaling pathways. TR6 may be a promising therapeutic reagent for mastitis treatment.
    Full-text · Article · Jan 2016 · International immunopharmacology
  • Source
    • "Furthermore, TLR4, but not TLR5, also induced IFNA and IFNB expression through IRF3 activation. These results are agreement with that both TLR4 and TLR5 initiate the MyD88-dependent pathway leading to NFKB activation, whereas TLR4, but not TLR5, also initiates the TRIF-dependent pathway that results in IRF3 activation[13]. Notably, a previous study showed that UPEC inhibited the proinflammatory cytokine expression by blocking MyD88-dependent pathway but induced IFNA and IFNB production via TRIF-dependent pathway in rat testicular cells[8]. The inhibition on the proinflammatory cytokine production in testicular cells favors the immunoprivileged environment in the testis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Uropathogenic E. coli (UPEC) may cause epididymitis and impair male fertility. The mechanisms underlying the innate immune responses to UPEC infection in the epididymis are not fully understood. This study showed that UPEC induced innate immune responses in mouse epididymal epithelial cells (EECs) through the activation of Toll-like receptor (TLR)4 and TLR5. UPEC infection significantly induced the expression of proinflammatory cytokines, including tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1, in EECs through the activation of nuclear factor kappa B. Moreover, UPEC induced the production of type 1 interferons by EECs through the activation of interferon regulatory factor 3. The UPEC-induced innate immune responses were significantly reduced in EECs of Tlr4 or Tlr5 knockout mice. The innate immune responses were further reduced in Tlr4 and Tlr5 double knockout EECs. Furthermore, we demonstrated that TLR4 and TLR5 cooperatively initiated the epididymal innate immune responses to UPEC infection in vivo. The results provide novel insights into the mechanisms underlying the epididymal innate immune responses to UPEC infection.
    Preview · Article · Jan 2016 · Biology of Reproduction
  • Source
    • "It has been ascribed physiological relevance in prevention and limitation of adverse and injurious inflammatory immune reactions[43,45]. In the context of Gram-positive and Gram-negative infection, inflammatory cytokine release is triggered via pattern recognition receptors, such as Toll-like receptors (TLR) 2 and 4[46]. Both TLRs have been implicated in inflammatory diseases including the pathogenesis of BPD47484950. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Surfactant replacement therapy is the standard of care for the prevention and treatment of neonatal respiratory distress syndrome. New generation synthetic surfactants represent a promising alternative to animal-derived surfactants. CHF5633, a new generation reconstituted synthetic surfactant containing SP-B and SP-C analogs and two synthetic phospholipids has demonstrated biophysical effectiveness in vitro and in vivo. While several surfactant preparations have previously been ascribed immunomodulatory capacities, in vitro data on immunomodulation by CHF5633 are limited, so far. Our study aimed to investigate pro- and anti-inflammatory effects of CHF5633 on native and LPS-stimulated human adult monocytes. Methods: Highly purified adult CD14+ cells, either native or simultaneously stimulated with LPS, were exposed to CHF5633, its components, or poractant alfa (Curosurf®). Subsequent expression of TNF-α, IL-1β, IL-8 and IL-10 mRNA was quantified by real-time quantitative PCR, corresponding intracellular cytokine synthesis was analyzed by flow cytometry. Potential effects on TLR2 and TLR4 mRNA and protein expression were monitored by qPCR and flow cytometry. Results: Neither CHF5633 nor any of its components induced inflammation or apoptosis in native adult CD14+ monocytes. Moreover, LPS-induced pro-inflammatory responses were not aggravated by simultaneous exposure of monocytes to CHF5633 or its components. In LPS-stimulated monocytes, exposure to CHF5633 led to a significant decrease in TNF-α mRNA (0.57 ± 0.23-fold, p = 0.043 at 4h; 0.56 ± 0.27-fold, p = 0.042 at 14h). Reduction of LPS-induced IL-1β mRNA expression was not significant (0.73 ± 0.16, p = 0.17 at 4h). LPS-induced IL-8 and IL-10 mRNA and protein expression were unaffected by CHF5633. For all cytokines, the observed CHF5633 effects paralleled a Curosurf®-induced modulation of cytokine response. TLR2 and TLR4 mRNA and protein expression were not affected by CHF5633 and Curosurf®, neither in native nor in LPS-stimulated adult monocytes. Conclusion: The new generation reconstituted synthetic surfactant CHF5633 was tested for potential immunomodulation on native and LPS-activated adult human monocytes. Our data confirm that CHF5633 does not exert unintended pro-inflammatory effects in both settings. On the contrary, CHF5633 significantly suppressed TNF-α mRNA expression in LPS-stimulated adult monocytes, indicating potential anti-inflammatory effects.
    Full-text · Article · Jan 2016 · PLoS ONE
Show more