The role of NLRC4 inflammasome in autoinflammatory diseases

Informazioni relative al progetto

INFLA-AID

ID dell’accordo di sovvenzione: 798068

DOI

10.3030/798068

Progetto concluso il 30 Settembre 2020

Data della firma CE 24 Aprile 2018

Data di avvio 1 Ottobre 2018

Data di completamento 29 Gennaio 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 172 800,00

Contributo UE

€ 172 800,00

Coordinato da

VIB VZW
Belgium

Periodic Reporting for period 1 - INFLA-AID (The role of NLRC4 inflammasome in autoinflammatory diseases)

Periodo di rendicontazione: 2018-10-01 al 2020-09-30

Sintesi del contesto e degli obiettivi generali del progetto

"Our immune system provides a protective mechanism to control and eliminate elements from pathogenic microbes and toxic substances. Upon bacterial infection, such as the foodborne illness caused by Salmonella, our innate immune system initiates an inflammatory response by activating ""inflammasomes"". These multiprotein platforms process proinflammatory cytokines, which are signalling molecules released into the extracellular matrix to resolve the infection.

Although inflammasome-mediated signalling pathways are highly regulated to avoid unwanted immune responses, a gain-of-function mutation in these pathways can cause hyperactivation of the inflammasome. This leads to overproduction of inflammasome-regulated cytokines and provokes autoinflammatory diseases (AID). Recently, gain-of-function mutations in the NLRC4 inflammasome have been attributed to the manifestation of NLRC4-associated AID (NLRC4-AID). In these patients, the onset of life-threatening systematic inflammation begins already at infancy. What is common amongst NLRC4-AID patients is their limited response to IL-1 inhibitors typically administered for AIDs. The objective of the INFLA-AID project is to identify how a mutation in the NLRC4 protein is causing such devastating AID by characterising some of the cellular and molecular mechanisms underlying the activation of the NLRC4 inflammasome."

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Upon completion of the INFLA-AID project, we have obtained new insights into NLRC4 inflammasome-mediated signalling pathway:

1. We obtained in vivo endogenous NLRC4 protein expression patterns to locate organs important for NLRC4-mediated inflammation.

2. Using NLRC4 mutant mice generated in the host laboratory, we observed that only certain types of cells showed mutation-mediated hyperactivation of the NLRC4 inflammasome signalling pathway that promoted significantly higher release of an inflammasome-generated cytokine.

Currently, the cell type specific upstream regulatory mechanisms of NLRC4 inflammasome signalling are being investigated in the context of healthy and the NLRC4-AID patients.

The results obtained from the INFLA-AID project have been presented in numerous international conferences for immunologists.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

This study will provide an insight into the mechanisms by which one mutation in the NLRC4 protein can sabotage our immune system and will contribute to a better understanding of inflammasomopathies.

By working closely with clinicians specialised in AIDs, we aim to delay disease onset and mitigate the symptoms in patients with aberrant NLRC4 inflammasome activities.

Furthermore, our findings will be of interest for immunologists as they highlight a unique characteristic of NLRC4 inflammasome that originates from its cell type-specific activation mechanism.

Inflammatory signalling outcomes of healthy or mutated NLRC4 inflammasome