Canonical and non-canonical functions of NLRP3

Since its discovery, NLRP3 is almost never separated from its major role in the protein complex it forms with ASC, NEK7 and Caspase-1, the inflammasome. This key component of the innate immune response mediates the secretion of proinflammatory cytokines IL-1β and IL-18 involved in immune response to microbial infection and cellular damage. However, NLRP3 has also other functions that do not involve the inflammasome assembly nor the innate immune response. These non-canonical functions have been poorly studied. Nevertheless, NLRP3 is associated with different kind of diseases probably through its inflammasome dependent function as through its inflammasome independent functions.

The study and understanding of the canonical and non-canonical functions of NLRP3 can help to better understand its involvement in various pathologies. In parallel, the description of the mechanisms of action and regulation of its various functions, can allow the identification of new therapeutic strategies.

NLRP3 functions have mainly been studied in the context of the inflammasome, in myeloid cells and in totally deficient transgenic mice. However, for several year, the work of different teams has proven that NLRP3 is also expressed in other cell types where it has functions that are independent of the inflammasome. If these studies suggest that NLRP3 could play different roles in the cytoplasm or the nucleus of the cells, the mechanisms underlying NLRP3 non-canonical functions remain unclear. This is why we propose in this review an inventory of the canonical and non-canonical functions of NLRP3 and their impact in different pathologies.