Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation

Abstract

Inflammation is part of the non-specific immune response that occurs in reaction to any type of bodily injury. In some disorders, the inflammatory process - which under normal conditions is self-limiting - becomes continuous and chronic inflammatory diseases might develop subsequently. Pattern recognition molecules (PRMs) represent a diverse collection of molecules responsible for sensing danger signals, and together with other immune components they are involved in the first line of defence. NALP3 and NOD2, which belong to a cytosolic subgroup of PRMs, dubbed Nod-like-receptors (NLRs), have been associated recently with inflammatory diseases, specifically Crohn's disease and Blau syndrome (NOD2) and familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (NALP3). The exact effects of the defective proteins are not fully understood, but activation of nuclear factor (NF)-kappaB, transcription, production and secretion of interleukin (IL)-1beta and activation of the inflammasome are some of the processes that might hold clues, and the present review will provide a thorough update in this area.

Fig. 1

Model for possible interactions between NOD2 and NALP3. Macrophages engulf and phagocytize bacteria; the peptidoglycan (PGN) present in the bacterial wall is degraded to produce muropeptides, which are similar to muramyl dipeptide (MDP). MDP can also be translocated into the cytoplasm by the hPepT1 transporter located in the brush border of colonocytes. In the cytoplasm, MDP is then able to activate NOD2, which in turn interacts with RIP2. This sequence of events activates nuclear factor (NF)-κB, which upon translocation to the nucleus induces, among others, pro-interleukin (IL)-1β transcription. Cytoplasmic MDP might also induce assembly of the NALP3 inflammasome, but bacterial RNA, toxins, uric acid crystals (*the mechanism by which uric acid crystals or its components become available in the cytoplasm is still unknown) and adenosine triphosphate (ATP) also trigger activation of the NALP3 inflammasome. The inflammasome holds 2 caspase-1 in close proximity, allowing cross-activation. Active caspase-1 is then able to process IL-1β. Mature pro-IL-1β is then released into the extracellular environment, together with caspase-1 (not shown). UAC: uric acid crystals; RNA refers to bacterial RNA; TOX: toxins.

Fig. 2

Structure of NOD2. NOD2 is comprised of two successive N-terminal caspase recruitment domain (CARD) domains; a central Nod-like receptor (NACHT) (NOD) domain, followed by a NACHT association domain (NAD) and C-terminal leucine-rich repeats (LRRs). The three major mutations associated with Crohn's disease affect the C-terminal portion.

Fig. 3

Structure of the NALP3 inflammasome. NALP3 assembles with apoptosis-associated speck-like protein containing a CARD (ASC) and CARDINAL. CARD domains in the two adaptor molecules are able to interact with caspase-1 CARD domains and hold 2 caspases in close proximity to allow cross-activation.