Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease

Lassen, Kara G.; Xavier, Ramnik J.

doi:10.1038/mi.2017.18

Cited by 25 publications

(24 citation statements)

References 144 publications

(135 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…And we will explore the underlying mechanisms of the changing LC3B, p62 with time prolonged in depth in further studies. In addition, activation of autophagy has been identified as cytoprotective in some settings, whereas in other cases, sustained or excessive activation of autophagy has been associated with inflammatory pathologies [ 32 , 33 ]. Recent investigations have shown that the phagocytic uptake of cells dying through autophagy induction in human macrophages evokes a pro-inflammatory response as characterized by the induction and secretion of cytokines such as TNF-α, IL-6, IL-8 and IL-10 [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury

et al. 2018

View full text Add to dashboard Cite

Background and aims Defective autophagy has been proposed as an important event in a growing number of autoimmune and inflammatory diseases such as rheumatoid arthritis and lupus. However, the precise role of mechanistic target of rapamycin (mTOR)-dependent autophagy and its underlying regulatory mechanisms in the intestinal epithelium in response to inflammation and oxidative stress remain poorly understood. Methods The levels of p-mTOR, LC3B, p62 and autophagy in mice and LPS-treated cells were examined by immunoblotting, immunohistochemistry, confocal microscopy and transmission electron microscopy (TEM). We evaluated the expression of IL-1β, IL-8, TNF-α, MDA, SOD and T-AOC by quantitative real time-polymerase chain reaction (qRT-PCR) and commercially available kits after silencing of mTOR and ATG5. In vivo modulation of mTOR and autophagy was achieved by using AZD8055, rapamycin and 3-methyladenine. Finally, to verify the involvement of TLR4 signalling and the NF-κB pathway in cells and active ulcerative colitis (UC) patients, immunofluorescence, qRT-PCR, immunoblotting and TEM were performed to determine TLR4 signalling relevance to autophagy and inflammation. Results The mTOR-dependent autophagic flux impairment in a murine model of colitis, human intestinal epithelial cells and active UC patients is probably regulated by TLR4-MyD88-MAPK signalling and the NF-κB pathway. Silencing mTOR remarkably attenuated, whereas inhibiting ATG5 aggravated, LPS-induced inflammation and oxidative injury. Pharmacological administration of mTOR inhibitors and autophagy stimulators markedly ameliorated experimental colitis and oxidative stress in vivo. Conclusions Our findings not only shed light on the regulatory mechanism of mTOR-dependent autophagy, but also provided potential therapeutic targets for intestinal inflammatory diseases such as refractory inflammatory bowel disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Such cross-talk may be particularly important in maintaining intestinal homeostasis, as witnessed in human allele variants in these components that are associated with inflammatory conditions such as Crohn’s disease (Parkes et al, 2007). The reader is referred to one of a number of excellent reviews that exist on this topic (Salem et al, 2015, Lassen and Xavier, 2017). …”

Section: Introductionmentioning

confidence: 99%

Innate Immunity to Intracellular Pathogens: Balancing Microbial Elimination and Inflammation

Mitchell

Isberg

2017

Cell Host & Microbe

101

View full text Add to dashboard Cite

Summary Recent excitement regarding immune clearance of intracellular microorganisms has focused on two systems that maintain cellular homeostasis. One system includes cellular autophagy components that mediate degradation of pathogens in membrane-bound compartments, in a process termed xenophagy. The second system is driven by interferon– regulated GTPases that promote rupture of pathogen-containing vacuoles and microbial degradation. In the case of xenophagy, pathogen sequestration and compartmentalization suppress inflammation. In contrast, interferon-driven events can lead to exposure of pathogen-associated molecular patterns to the host cytosol with consequent inflammasome activation. Paradoxically, signals and factors involved in xenophagy also mobilize interferon-regulated GTPases, which drive the inflammatory response, indicating considerable crosstalk between these pathways. How these responses are prioritized remains to be understood. In this review, we describe mechanisms of intracellular pathogen clearance that rely on the autophagy machinery and interferon-regulated GTPases, and speculate how these pathways engage each other to balance pathogen elimination with inflammation.

show abstract

“…Macroautophagy is distinguished from the two other primary types of autophagy in mammalian cells, microautophagy and chaperone-mediated autophagy, by the formation of a double membrane bound phagophore and autophagosome ( 83 ). In its most basic form, autophagy represents a cellular adaptation to starvation and allows the non-specific breakdown of a cell’s own constituents to recycle nutrients and balance biosynthetic pathways ( 84 , 85 ). This form of autophagy, known as non-selective autophagy, is also induced by cellular stress.…”

Section: Innate Immune Modulation Of Autophagymentioning

confidence: 99%

Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease

et al. 2018

View full text Add to dashboard Cite

Activation of the innate immune system through pattern-recognition receptor (PRR) signaling plays a pivotal role in the early induction of host defense following exposure to pathogens. Loss of intestinal innate immune regulation leading aberrant immune responses has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The precise role of PRRs in gut inflammation is not well understood, but considering their role as bacterial sensors and their genetic association with IBD, they likely contribute to dysregulated immune responses to the commensal microbiota. The purpose of this review is to evaluate the emerging functions of PRRs including their functional cross-talk, how they respond to mitochondrial damage, induce mitophagy or autophagy, and influence adaptive immune responses by interacting with the antigen presentation machinery. The review also summarizes some of the recent attempts to harness these pathways for therapeutic approaches in intestinal inflammation.

show abstract

Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease

Cited by 25 publications

References 144 publications

Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury

Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury

Innate Immunity to Intracellular Pathogens: Balancing Microbial Elimination and Inflammation

Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease

Contact Info

Product

Resources

About