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.

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    • "However, prolonged stimulation of TLRs (by abundant TLR-interacting mycobacterial compounds) results in the production of immunosuppressive cytokines, decreased antigen presentation and survival of bacteria inside macrophages (Saraav et al. 2014). Nevertheless, TLR-4-mediated autophagy was found to promote mycobacteria containment in macrophages (Xu et al. 2007). Finding the right equilibrium of different TLRs activation using either drug or vaccine approaches might lead to increased immunogenic response and improved TB therapies. "
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    ABSTRACT: Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB.
    DNA and cell biology 01/2015; 34(4):1-15. DOI:10.1089/dna.2014.2745 · 1.99 Impact Factor
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    • "This was originally described for TLRs (Delgado et al., 2008). TLR2, 4 and 7 stimulation have been primarily found to upregulate macroautophagy (Xu et al., 2007; Delgado et al., 2008; Romao et al., 2013). TLR4 engages upon recognition of lipopolysaccharides (LPS) in bacterial cell walls the two adaptor molecules MyD88 and TRIF, which have been shown to bind to Atg6/Beclin-1 to upregulate macroautophagy (Shi and Kehrl, 2008). "
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    ABSTRACT: Innate immune responses are the first line of defense for an organism to restrict invading pathogens. They fulfill two main functions, namely detection of the pathogen to successively alarm the appropriate components of the immune system and early inhibition of the infection to prevent demise of the infected organism before a more tailored immune response, usually mediated by the adaptive immune system, can be mounted. Autophagy and phagocytosis, modified by the autophagic core machinery, contribute to these functions by regulating pathogen detection, influencing the production of innate immune mediators and directly restricting intracellular and extracellular pathogens as an effector mechanism of innate immunity. These aspects of the involvement of mainly macroautophagy in innate immune responses will be discussed in this review.
    Cellular Microbiology 09/2014; 16(11). DOI:10.1111/cmi.12358 · 4.82 Impact Factor
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    • "Also, the expression of a well known sensor of autophagy i.e. toll like receptor 4 [50] was determined and its down expression in morin hydrate treated cells was accounted which was overexpressed in LPS alone treated cells. Thus LPS treatment induced autophagy via TLR4–Beclin-1 dependent pathway which was suppressed by morin hydrate treatment [50]. On the other hand, LPS also induced elevated expression of ULK1 and TSC2. "
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    ABSTRACT: Morin, a natural flavonoid that is the primary bioactive constituent of the family Moraceae, has been found to be associated with many therapeutic properties. In this study, we evaluated the immunomodulatory activities of increasing concentration of morin hydrate in vitro. Three different concentrations of morin hydrate (5, 10, and 15μM) were used to evaluate their effect on splenocyte proliferation, phagocytic activity of macrophages, cytokine secretion and complement inhibition. We also evaluated the role of morin hydrate on lipopolysaccharide (LPS) induced autophagy. Our study demonstrated that morin hydrate elicited a significant increase in splenocyte proliferation and phagocytic capacity and suppressed the production of cytokines and nitric oxide in activated macrophages. Humoral immunity measured by anti-complement activity showed an increase in inhibition of the complement system after the addition of morin hydrate, where morin hydrate at 15μM concentration induced a significant inhibition. Depending on our results, we can also conclude that morin hydrate protects macrophages from LPS induced autophagic cell death. Our findings suggest that morin hydrate represents a structurally diverse class of flavonoid and this structural variability can profoundly affect its cell-type specificity and its biological activities. Supplementation of immune cells with morin hydrate has an upregulating and immunoprotective effect that shows potential as a countermeasure to the immune dysfunction and suggests an interesting use in inflammation related diseases.
    International Immunopharmacology 07/2014; 22(2):356-65. DOI:10.1016/j.intimp.2014.07.020 · 2.71 Impact Factor
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