Toll-like Receptor 4 Is a Sensor for Autophagy Associated with Innate Immunity

Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Immunity (Impact Factor: 19.75). 08/2007; 27(1):135-44. DOI: 10.1016/j.immuni.2007.05.022
Source: PubMed

ABSTRACT Autophagy has recently been shown to be an important component of the innate immune response. The signaling pathways leading to activation of autophagy in innate immunity are not known. Here we showed that Toll-like receptor 4 (TLR4) served as a previously unrecognized environmental sensor for autophagy. Autophagy was induced by lipopolysaccharide (LPS) in primary human macrophages and in the murine macrophage RAW264.7 cell line. We defined a new molecular pathway in which LPS-induced autophagy was regulated through a Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-dependent, myeloid differentiation factor 88 (MyD88)-independent TLR4 signaling pathway. Receptor-interacting protein (RIP1) and p38 mitogen-activated protein kinase were downstream components of this pathway. This signaling pathway did not affect cell viability, indicating that it is distinct from the autophagic death signaling pathway. We further showed that LPS-induced autophagy could enhance mycobacterial colocalization with the autophagosomes. This study links two ancient processes, autophagy and innate immunity, together through a shared signaling pathway.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is a conserved pathway that sequesters cytoplasmic material and delivers it to lysosomes for degradation. Digestion of portions of the cell interior plays a key role in the recycling of nutrients, remodeling, and disposal of superfluous organelles. Along with its metabolic function, autophagy is an important mechanism for innate immunity against invading bacteria and other pathogens. Multicellular organisms seem to have exploited autophagy to eliminate intracellular pathogens that would otherwise grow in the cytoplasm. Surprisingly, autophagy is involved in the response to extracellular pathogens as well, following their engulfment by conventional phagocytosis. Possible links between these two forms of cellular "eating" represent a new dimension in host defense.
    Autophagy 07/2008; 4(5):607-11. DOI:10.4161/auto.6397 · 11.42 Impact Factor
  • Developments in Precambrian Geology, pages 841-853;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Overview. Bowen's disease, squamous cell carcinoma in situ, is a relatively common pre-malignant lesion usually treated by surgery, curettage or cryotherapy, although no modality is ideal. Topical ALA-PDT has also been shown to be effective with clearance rates of 90–100%. This chapter assesses the evidence and compares ALA-PDT with conventional therapies.Summary. Despite variation in the treatment parameters of reported studies, improved outcome is associated with 3–6 hour application times for 20% 5-ALA and the use of narrowband red light. Randomised comparison studies indicated ALA-PDT to be at least as effective as cryotherapy and topical 5-fluorouracil, but with fewer adverse reactions. In addition to achieving high clearance rates, tissue preservation, absence of ulceration and failure to heal, along with a uniformly high standard of cosmesis, support the use of ALA-PDT in clinical practice. Recurrence rates of 0–10% over 12–36 months compare favourably with historical data for conventional therapies.Implications. Although all patches of Bowen's can respond, ALA-PDT is probably best suited to large and multiple lesions, and single patches in sites where standard therapies risk complications.Future directions. Further studies are required to confirm the optimal treatment parameters, but ALA-PDT is now proposed as a good choice in therapy guidelines for Bowen's disease. The development of 5-ALA esters and refinement of light sources aim to improve the efficacy of single treatment ALA-PDT in Bowen's disease.
Show more