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

Xu, Yi; Jagannath, Chinnaswamy; Liu, Xian De; Sharafkhaneh, Amir; Kołodziejska, Katarzyna; Eissa, N. Tony

doi:10.1016/j.immuni.2007.05.022

Cited by 810 publications

(823 citation statements)

References 33 publications

(57 reference statements)

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“…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‐1β, while activators, like ATP, are required to assemble the NLRP3 inflammasome and initiate the subsequent activation of IL‐1β and IL‐18.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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“…In macrophages, signaling mediated by TLR ligands can trigger autophagy, although the mechanism remains largely unknown (28,29). Mounting evidence indicates that the protein level of Beclin 1 in cells is crucial for autophagy induction (30).…”

Section: Discussionmentioning

confidence: 99%

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

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The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.

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“…LPS treatment of the RAW264.7 macrophage cell line increases GFP-LC3 puncta when visualised by fluorescence microscopy, suggesting autophagy induction (Xu et al, 2007). In this case, initiation of autophagy is dependent on LPS recognition by TLR4, as determined by Tlr4 siRNA knockdown or transfection with a mutant dominant-negative TLR4 (Xu et al, 2007). Other examples also demonstrate autophagy induction upon TLR agonist recognition.…”

Section: Regulation Of Autophagymentioning

confidence: 95%

“…LC3 co-localization with phagocytosed zymosan also requires TLR2 signalling, where LC3 does not co-localize with zymosan in Tlr2-deficient macrophages (Sanjuan et al, 2007). LPS treatment of the RAW264.7 macrophage cell line increases GFP-LC3 puncta when visualised by fluorescence microscopy, suggesting autophagy induction (Xu et al, 2007). In this case, initiation of autophagy is dependent on LPS recognition by TLR4, as determined by Tlr4 siRNA knockdown or transfection with a mutant dominant-negative TLR4 (Xu et al, 2007).…”

Section: Regulation Of Autophagymentioning

confidence: 99%

Intersection of autophagy with pathways of antigen presentation

Patterson

Mintern

2012

Protein Cell

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Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

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

Cited by 810 publications

References 33 publications

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Intersection of autophagy with pathways of antigen presentation

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