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THE NLRP3 INFLAMMASOME IS UPREGULATED ON MRNA EXPRESSION LEVEL AND ACTIVATED ON PROTEIN LEVEL IN INFLAMMATORY BOWEL DISEASE PATIENTS IN A SYSTEMATIC META-ANALYSIS AND IN A NEW OBSERVATIONAL STUDY COHORT

Paula Metselaar 1, Roos Menke 1, Nikolas Seretis 1, Roos Schilder 1, Wouter J. de Jonge 1, Mark Löwenberg 1, Anje te Velde 1

Affiliations

1 Amsterdam UMC, Amsterdam, Netherlands

Summary

AI Generated

A meta-analysis and observational cohort study found NLRP3 and IL1B gene expression significantly elevated in IBD patients versus controls and in active versus quiescent disease, but IL-1β and IL-18 protein production showed large individual variation unrelated to disease activity.

Meta-analysis of thirty studies showed NLRP3 and IL1B mRNA expression significantly higher in IBD patients than non-IBD controls and higher in active disease than remission
In an observational cohort of 70 CD and UC patients, ex vivo LPS and ATP stimulation activated NLRP3-related genes and cytokine secretion, which was blocked by the NLRP3 inhibitor MCC950
While inflammasome transcription was elevated in active IBD, IL-1β and IL-18 protein production showed large individual variation not related to disease activity
Individual variance in NLRP3 inflammasome activation could help identify IBD patients who might benefit from NLRP3- or IL-1β-directed therapies
This material is relevant for researchers and clinicians interested in IBD pathophysiology and personalized therapeutic approaches

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are non-infectious chronic inflammatory disorders of the gastro-intestinal tract. The continuous presence of inflammatory stimuli, such as increased circulation of cytokines and danger-associated molecular patterns (DAMPs), leads to an enhanced immune response in these patients that could explain some types of disease relapse. An important receptor for DAMPS and pathogen-associated molecular patterns (PAMPs) is NLRP3, a cytosolic pattern recognition receptor. The NLRP3 inflammasome is exclusively activated by inflammatory stimuli, like DAMPs and PAMPs, and therefore not expressed without inflammation. It is thought that NLRP3 associates with ASC to recruit pro-Caspase 1 to the NLRP3 inflammasome and cleave it to its active form. In turn, Caspase 1 cleaves pro-interleukin 1 beta (IL-1β) and pro-interleukin 18 (IL-18) to their mature forms. IL-1β is a known elevated pro-inflammatory cytokine in IBD, promoting intestinal inflammation and immune cell recruitment. We hypothesized that the NLRP3 inflammasome pathway is therefore upregulated in IBD patients.

Aims & Methods

We first set out to systematically analyze gene expression of NLRP3 and IL1B in IBD patients by performing a systematic literature review and subsequent meta-analysis according to the PRISMA guidelines and Cochrane Collaboration methods. Subsequently, an observational cohort of 70 active and quiescent patients with CD or UC was sampled for whole blood, to study NLRP3 inflammasome gene regulation, protein production, assembly and secretion. We performed ex vivo LPS and ATP challenges of whole blood, with and without NLRP3 inflammasome formation inhibitor MCC950.

Results

Across thirty studies with publicly available mRNA expression data, we found NLRP3 and IL1B expression to be significantly higher in IBD patients than in non-IBD controls. In fresh IBD patient-derived whole blood, LPS and ATP stimulation activated the NLRP3-related genes, protein production and subsequent cytokine secretion. No IL-1β and IL-18 were secreted upon incubation with MCC950, suggesting a crucial role for NLRP3 inflammasome assembly in IL-1β and IL-18 production in immune cells. In patients with active IBD, the inflammasome was transcribed at a higher level than in patients in remission. However, this effect was lost on the protein level. We found a large spread in IL-1β and IL-18 production, suggesting a variation in activation of the NLRP3 inflammasome between individuals which was not related to disease activity.

Conclusion

NLRP3 and IL1B mRNA transcription is significantly increased in IBD patients compared to non-IBD controls, and significantly higher in patients with active disease than in patients in remission. While this fits the inflammatory state of active IBD, we found that the level of IL-1β and IL-18 production by the NLRP3 inflammasome is not significantly different between disease states. This suggests a variance in individual immune response to challenges, that could help identify a subset of IBD patients that would benefit from additional therapies directed at NLRP3 and IL-1β.

Conference

UEG Week Copenhagen 2023

Topics

IBD

Submission format

Abstract

Session

PP 05 IBD (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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ADD-ON MULTIPLE SUBMUCOSAL INJECTIONS OF RNA OLIGONUCLEOTIDE GUT-1 TO TUMOR NECROSIS FACTOR-ANTAGONIST TREATMENT IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: AN INVESTIGATOR-INITIATED TRIAL

Kenji Suzuki 1, Yukinori Sameshima 2, Junji Yokoyama 1, Shuji Terai 1, Hiroyuki Yoneyama 3, Raja Atreya 4, Markus F. Neurath 5, Toshifumi Hibi 6, Hitoshi Asakura 1

Affiliations

1 Niigata University Medical and Dental Hospital, Niigata, Japan

2 Sameshima Hospital, Kagoshima, Japan

3 GUT Inc., Kochi, Japan

4 University Erlangen-Nuremberg, Erlangen, Germany

5 University of Erlangen-Nuremberg, Erlangen, Germany

6 Kitasato University, Tokyo, Japan