Article

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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    • "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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    • "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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