Enigmatic inflammasomes

Inflammasomes are generally thought of as large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection; once activated, they trigger production of inflammatory cytokines and drive cells towards a pro-inflammatory death - termed pyroptosis. Inflammasome activation is a two-step process; priming or Signal 1 (typically via Toll or other receptors that activate NF-kB) induces transcription of pro-forms of IL-1β and IL-18, while activation or Signal 2 (by many effectors, including a number of bacterial toxins that form pores in cell membranes) comprises activation of caspase-1 in the inflammasome that in turn cleaves pro-IL-1β and pro-IL-18 and induces release of the active pro-inflammatory cytokines. The most studied inflammasome is the NLRP3 inflammasome, but in addition to NLRP3, there are several lesser-known or enigmatic inflammasomes whose functions seem to range from non-canonical inflammasome activation, pathogen/damage, suppression or modulation of inflammation and even embryonic development. In this review series, which will be presented in two parts, we will focus on lesser-known inflammasomes, such as NLRP6 (non-canonical inflammasome activation), NLRP9 (restricting rotavirus infection in intestinal epithelial cells), NLRX1 (negative regulators of inflammation), NLRC5 (regulating antigen presentation) and NLRP7 (sensing of bacterial lipoproteins). Although the function of NLRP3 is understood, the functions of these lesser-studied inflammasomes are largely unstudied. Given that after a decade of research, new inflammasome and new inflammasome activators are still being discovered indicates that there is a lot more that we need to find out in the NLR field. Only by understanding all of the members of the NLR family, will we be able to target them therapeutically in the future.