Inflammasomes bridge signaling between pathogen identification and the immune response

Abstract

Microbial organisms express pathogen-associated molecular patterns (PAMPs) that can stimulate expression of proinflammatory mediators following ligation of pathogen recognition receptors. However, both commensal organisms and pathogens can express PAMPs. The immune system can distinguish between commensals and pathogens in part through secretion of the key inflammatory cytokines interleukin (IL)-1beta and IL-18. A PAMP such as lipopolysaccharide can induce production of intracellular pro-IL-1beta and pro-IL-18, but not their secretion. A second "danger signal", derived from host-cell molecules that are released from stressed or infected cells, or detected as a PAMP that is present in the cytosol, can stimulate assembly of an inflammasome that activates the protease caspase-1. Caspase-1, in turn, is responsible for processing and secretion of the mature IL-1beta and IL-18. Many diverse ligands leading to inflammasome activation have been identified, but the cell signaling pathways initiated by the ligands tend to converge on a small set of common mechanisms.

Figure 1

Both a pathogen recognition receptor (PRR) and Nod-like receptor (NLR) family member are usually required for secretion of IL-1β. Binding of a pathogen-associated molecular patterns (PAMP) to its PRR results in pro-IL-1β synthesis, but not always secretion of IL-1β. A second signal, derived from an extracellular “danger signal” such as ATP or gout crystals, or an intracellular PAMP such as muramyl-dipeptide (MDP) from peptidoglycan activate an inflammasome consisting of caspase-1, the adaptor protein ASC, and a NLR family member or AIM2. LT, lethal toxin from Bacillus anthracis; dsDNA, double-stranded DNA. Inflammasome-dependent caspase-1 activation results in processing and secretion of the mature IL-1β.

Figure 2

Diverse danger signals lead to NLRP3 inflammasome activation through common mechanisms. Extracellular damage-associated molecular patterns (DAMPs) can lead to K+ efflux and then ROS production, or directly to ROS production. Large particles can also cause lysosomal destabilization and release of enzymes such as cathepsin B. Either high ROS levels or cytosolic cathepsin B can stimulate the NLRP3 inflammasome, leading to caspse-1 activation.