Activation of the NLRP3 inflammasome in health and disease

Abstract

The NOD-like receptor family pyrin domain containing (NLRP) 3 inflammasome is an important component of the innate immune response activated by pathogens and cellular damage. It serves as an activation platform for caspase-1, which controls the bioactivity of interleukin (IL)-1β. Classical activation of the NLRP3 inflammasome requires a priming step, followed by a subsequent signal, such as K+efflux, to induce NLRP3 activation and inflammasome assembly. Upon activation, caspase-1 cleaves gasdermin D (GSDMD) leading to the formation of membrane pores which serve as conduits for IL-1β release and induce pyroptosis. However, primary human monocytes engage an alternative pathway upon stimulation of toll-like receptor (TLR) 4. This pathway involves caspase-8 dependent NLRP3 activation leading to the release of IL-1β independently of K+ efflux and pyroptosis.

The NLRP3 inflammasome has been implicated in the pathogenesis of many inflammatory diseases. Initially, this work aimed to explore the role of the NLRP3 inflammasome in rheumatoid arthritis (RA) and to investigate the regulation of sterile α and HEAT/Armadillo motif containing protein (SARM1), a negative regulator of 3 NLRP3. However due to the COVID-19 pandemic and consequently a lack of access to RA samples, the project moved to investigate the expression of host response genes in convalescent COVID-19 participants, where NLRP3 was found to be elevated in monocytes 3-6 months following SARS-CoV-2 infection.

In summary, the alternative NLRP3 inflammasome pathway is shared by TLR family members in primary human monocytes. Furthermore, these data indicate that despite an absence of pyroptosis, TLR-induced IL-1β is potentially released through low level GSDMD pore formation. Consequently, monocytes remain functionally active enabling them to sustain the immune response supporting the clearance of an infection. Furthermore, elevated NLRP3 expression following SARS-CoV-2 infection may alter the inflammatory threshold for activation of monocytes in individuals recovered from COVID-19.

Date of Award	May 2022
Original language	English
Awarding Institution	University of Brighton
Supervisor	Sandra Sacre (Supervisor), Melanie Flint (Supervisor) & Lisa Mullen (Supervisor)