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

Corridoni, Daniele; Chapman, Thomas; Ambrose, Tim; Simmons, Alison

doi:10.3389/fmed.2018.00032

Cited by 37 publications

(26 citation statements)

References 285 publications

(322 reference statements)

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“…NOD2 remains the most strongly associated Crohn’s disease susceptibility gene (66,67). NOD2 polymorphisms (R702W, G908R, and 1007fs) in Crohn’s are often associated with disease states affecting the terminal ileum and contributing to stricturing and fibrostenosing disease requiring surgical intervention (68).…”

Section: Discussionmentioning

confidence: 99%

NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses

Corridoni

Shiraishi

Chapman

et al. 2019

Preprint

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NOD2 and TLR2 recognize components of bacterial cell wall peptidoglycan and direct defense against enteric pathogens. CD8 + T cells are important for immunity to such pathogens but how NOD2 and TLR2 induce antigen specific CD8 + T cell responses is unknown. Here, we define how these pattern recognition receptors (PRRs) signal in primary dendritic cells (DCs) to influence MHC class I antigen presentation. We show NOD2 and TLR2 phosphorylate PI31 via TBK1 following activation in DCs. PI31 interacts with TBK1 and Sec16A at endoplasmic reticulum exit sites (ERES), which positively regulates MHC class I peptide loading and immunoproteasome stability. Following NOD2 and TLR2 stimulation, depletion of PI31 or inhibition of TBK1 activity in vivo impairs DC cross-presentation and CD8 + T cell activation.DCs from Crohn's patients expressing NOD2 polymorphisms show dysregulated crosspresentation and CD8 + T cell responses. Our findings reveal unidentified mechanisms that underlie CD8 + T cell responses to bacteria in health and in Crohn's. KeywordsInnate Immunity, NOD2, TLR2, Cross-presentation, CD8 + T cells, Crohn's Disease PRR engagement increases CD8 + T cell activation by cross-presented peptides, but the molecular mechanisms underlying these effects are not completely defined (22,23,4,24,19,25,26). TLR4dependent phosphorylation of phagosomal SNAP-23 recruits MHC class I molecules from endosomal recycling compartments to phagosomes, which promotes cross-presentation (27). However, the mechanisms by which either NOD2 or TLR2 signal to the MHC class I antigen presentation machinery to enhance CD8 + T cell activation remain unclear. We hypothesized undertaking an unbiased screen of NOD2 and TLR2 signaling in primary DCs would reveal molecules co-opted by these receptors to enable cross-presentation. Utilizing information obtained from a quantitative phosphoproteomic analysis comparing NOD2 and TLR2 signaling in human DCs, we discovered that NOD2 in combination with TLR2 phosphorylates PI31. This signaling pathway links PI31 with defective cross-presentation as found in Crohn's. Materials and Methods Study DesignThe objective of this study was to explore the role of NOD2 and TLR2 in cross-presentation in human dendritic cells undertaking an unbiased screen. We have used a quantitative phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by a computational analysis to identify the proteins as differentially abundant in response to NOD2 and TLR2 sensing. Validation of the phosphoproteomic analysis was performed by the detection of proteins in phosphoenriched lysates and detected by western blot.Techniques for the modulation of gene expression (shRNA and siRNA) were used to confirm the results of observational studies. Immunoprecipitation, in-gel or in-solution digestions and HLAassociated peptide purification were all performed in primary DCs isolated from healthy donors and analysed on an ultra-high performance liquid chromatography system. Cellular analysis of cross-presentation e...

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Section: Discussionmentioning

confidence: 99%

NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses

Corridoni

Shiraishi

Chapman

et al. 2019

Preprint

Self Cite

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“…These signalling cascades originate at the extracellular and intracellular sensors and “splash” onto genes’ regulome (Figure A,C). Intracellular sensors, NOD receptors, inflammasomes and STING receptors are activated …”

Section: Proinflammatory Transcriptional Cascades Carry Signals To Thmentioning

confidence: 99%

“…Intracellular sensors, NOD receptors, inflammasomes and STING receptors are activated. 48,[54][55][56][57][58][59][60]…”

Section: Transcriptional Cascades Carry Signals To the Nucleus In Resmentioning

confidence: 99%

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Hawiger

Zienkiewicz

2019

Scand J Immunol

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Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic and physical insults that produce distinct types of inflammatory responses. This aetiologic view of inflammation informs its classification based on a cause‐dependent mechanism as well as a cause‐directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the centre of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non‐immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors’ access to the nucleus. We present two approaches that control proinflammatory signalling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signalling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell‐penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the nine genes required for metabolic responses. We compare these emerging anti‐inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical and other types of inflammation afflicting millions of people worldwide.

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“…Damaged mitochondria result in elevated levels of ROS within the intestinal epithelium, which play a key role in intestinal inflammation occurrence and in DNA, proteins or lipids damage [ 59 , 60 ]. Therefore, mitophagy is responsible for suppression of NLRP3 inflammasome activation by removing injured mitochondria, hence limiting the release of ROS and mtDNA [ 61 ]. Since autophagy has also been correlated with a low level of ROS, loss of autophagy favors production of mtROS, which in turn enhances NLRP3 inflammasome activation [ 38 , 46 ].…”

Section: Autophagymentioning

confidence: 99%

Interplay between Cellular and Molecular Mechanisms Underlying Inflammatory Bowel Diseases Development—A Focus on Ulcerative Colitis

Samoilă

Dinescu

Costache

2020

Cells

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Inflammatory bowel diseases (IBD) are defined by the continuous inflammation of the gastrointestinal tract. During inflammation, the number of pathogens in the intestinal epithelium increases, leading to inflammasome assembly. Inflammasome activation is meant to protect the intestinal epithelial barrier from further damage by maintaining homeostasis. Although its purpose is to protect the cells, excessive nucleotide-binding oligomerization domain-like receptor and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly is responsible for the synthesis of a high number of pro-inflammatory cytokines. The activation of two crucial pathways, autophagy process, and unfolded protein response, is initiated for restoring homeostasis. Aberrant expression of miRNAs and lncRNAs also interfere with the pathogenic mechanisms of IBD, as these non-coding transcripts play key roles in regulation of biological processes, such as inflammation and immunity. This review thoroughly describes the cellular and molecular mechanism that trigger and perpetuate inflammation in ulcerative colitis (UC) patients.

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

Cited by 37 publications

References 285 publications

NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses

NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

Interplay between Cellular and Molecular Mechanisms Underlying Inflammatory Bowel Diseases Development—A Focus on Ulcerative Colitis

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