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,
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    • "Recent studies have led to an appreciation of the role of autophagy as an elementary form of innate immunity against invading micro-organisms in eukaryotes (Deretic et al., 2013). LPS induces autophagy in macrophages (Sanjuan et al., 2007; Xu et al., 2007), providing a means to clear invasive bacteria. There are different stimuli for inflammation: a stimulus like the TLR ligand LPS induces expression of pro-IL-1b, while activators, like ATP, are required to assemble the NLRP3 inflammasome and initiate the subsequent activation of IL-1b and IL-18. "
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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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    • "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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