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: 21.56). 08/2007; 27(1):135-44. DOI: 10.1016/j.immuni.2007.05.022
Source: PubMed


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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Available from: Chinnaswamy Jagannath, Oct 06, 2015
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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 · 2.06 Impact Factor
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    • "This leads to enhanced TRAF6 E3 ligase activity, which results in the K63-linked ubiquitination of Beclin 1 and the oligomerization of Beclin 1. This promotes the activation of PI(3)K and helps the formation of autophagosomes [42, 43]. Another study [44] reported that heat shock protein 90 (HSP90) plays an important role in mediating TLR4-induced autophagy. "
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    ABSTRACT: Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper.
    BioMed Research International 09/2014; 2014:297293. DOI:10.1155/2014/297293 · 2.71 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 · 4.92 Impact Factor
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