Characterising ferritin as a danger-associated molecular pattern in inflammasome-mediated inflammation in acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a highly inflammatory condition with high mortality. There is evidence of inflammasome activity in ARDS patients, including NLRP3 inflammasome activation. NLRP3 activation requires two signals, termed priming and activation. The priming and activation signals can be from pathogen-associated or danger-associated molecular patterns (PAMPS and DAMPS). Activation of the NLRP3 inflammasome leads to downstream processing and release of interleukin (IL)-1β and IL-18, as well as gasdermin-mediated lytic cell death termed pyroptosis. Evidence has emerged that increased serum levels of the iron-storage protein ferritin may be associated with IL-18 and increased mortality in ARDS patients. Ferritin is made up of a tissue-dependent ratio of heavy (FTH) and light (FTL) chain subunits. Ferritin is traditionally thought of as an acute phase protein. However, the FTH subunit has immunomodulatory properties on human macrophages.

This thesis tested : (1) human FTH may be a DAMP that primes or activates NLRP3, (2) ferritin triggers inflammatory cascades through interaction with PRRs on macrophages, and (3) inflammasome activation in ARDS is associated with elevated ferritin.

Findings demonstrate that FTH functions as a DAMP, priming the NLRP3 inflammasome in human macrophages. In addition, FTH stimulation induced significant gene transcription and cytokine secretion. In ARDS patients, bronchoalveolar lavage fluid and serum showed evidence of inflammasome activation and elevated ferritin, absent in healthy controls.

This thesis demonstrates that FTH in ferritin is a DAMP which is not merely a consequence of inflammation, but instead a driver of inflammation. These findings suggest ferritin and the NLRP3 inflammasome as promising therapeutic targets for ARDS.

Thesis is embargoed until 31 December 2028.

Date of Award	Dec 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Rebecca Coll (Supervisor) & Danny McAuley (Supervisor)