Inflammasome activation

A complementing system of pattern recognition receptors (PRRs), called the NOD-like receptor (NLR) superfamily, is found in the cytoplasm of innate immune cells. Some NLR members, such as the NLRP3, form inflammasomes that regulate maturation of the inactive cytokines pro-IL-1β and pro-IL-18 by activating caspase-1. Mature IL-1β and IL-18 are potent, multifunctional, pro-inflammatory cytokines. Extracellular ATP, hyperglycemia, reactive oxygen species (ROS), crystals, lysosomal damage, and bacterial toxins are examples of stimuli that activate NLR-containing inflammasomes.

In humans, 23 NLR molecules are identified, but only a fraction of these have a known function, and NLRP3 and NLRC4 (Ipaf) are the most extensively studied.

By using mice with a targeted deletion of NLRP12, which is a poorly described NLR, we have found a novel inflammasome action mediated by this protein. Our results suggest that NLRP12 may pair with Asc to form active caspase-1 that controls release of IL-1β and IL-18 when challenged by the causative agent of the plague, Yersinia pestis (Lien et al., The NLRP12 Inflammasome Recognizes Yersinia pestis. Immunity. Elsevier Inc; 2012;37:96–107).

Aim:

In this programme we hope to establish the molecular basis for inflammasome activation leading to maturation of IL-1β and IL-18 in sterile and non-sterile inflammation.