Nutraceutical Compounds Targeting Inflammasomes in Human Diseases

Abstract

The macromolecular complex known as "inflammasome" is defined as an intracellular multi-protein complex composed of a sensor receptor (PRR), an adaptor protein and an effector enzyme (caspase-1), which oligomerize when they sense danger, such as how the NLR family, AIM-2 and RIG-1 receptors protect the body against danger via cytokine secretion. Within the NLR members, NLRP3 is the most widely known and studied inflammasome and has been linked to many diseases. Nowadays, people's interest in their lifestyles and nutritional habits is increasing, mainly due to the large number of diseases that seem to be related to both. The term "nutraceutical" has recently emerged as a hybrid term between "nutrition" and "pharmacological" and it refers to a wide range of bioactive compounds contained in food with relevant effects on human health. The relationship between these compounds and diseases based on inflammatory processes has been widely exposed and the compounds stand out as an alternative to the pathological consequences that inflammatory processes may have, beyond their defense and repair action. Against this backdrop, here we review the results of studies using several nutraceutical compounds in common diseases associated with the inflammation and activation of the NLRP3 inflammasomes complex. In general, it was found that there is a wide range of nutraceuticals with effects through different molecular pathways that affect the activation of the inflammasome complex, with positive effects mainly in cardiovascular, neurological diseases, cancer and type 2 diabetes.

Keywords: NLRP3 inflammasomes; cancer; cardiovascular diseases; health; immune system; neurological diseases; nutraceuticals; type 2 diabetes.

Figure 1

Cellular pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are transmembrane receptors expressed in cellular and endosomal membranes, which are comprised of 10 members in human beings. They each recognize distinct pathogen-associated molecular patterns (PAMPS) derived from various microbial pathogens, such as viruses, fungi, bacteria and protozoa. TLRs are detected via the LRRdomain and a signal is sent through intracellular space via the TIR domain. Retinoic acid inducible gene-I (RIG1)-like receptors (RLRs) detect RNA and activate the helicase domain or the kinase domain. There are two intracellular detectors of DNA called DAI and AIM2. Nucleotide-binding-and-oligomerization-domain (NOD)-like receptors (NLRs) belong to a very large family of intracellular PRRs, whilst c-type lectin receptors (CLRs) belong to a large family of proteins, which play an essential role in antifungal immunity. Only a few CLRs function as PRRs, for instance Dectin-1 and MICL, by recognizing carbohydrate ligands from pathogens. Signals are transmitted through the N-terminal domain.

Figure 2

Mechanisms of NLRP3 activation. There are two consecutive signals that are needed in order to have an activated inflammasome. The first is responsible for the activation of the NF_Ϗβ pathway and upregulating inactive pro-inflammatory cytokines such as IL-1β and IL-18, as well as transcribing NLRP3 proteins. The second signal carries out the recruitment of apoptosis-associated speck-like protein (ASC) and pro-caspase-1 and the NLRP3 oligomerization. Then, the pro-inflammatory cytokines are activated and released into extracellular space. Within the NLRP3 ligands, extracellular ATP, K⁺ efflux and Ca⁺² trigger the inflammasome through the Pannexin-1, P2 × 7 and TRMP2 receptors. Exogenous particulate matter destabilizes and damages lysosomes and thus, numerous inner enzymes such as cathepsin B are released into the cytoplasm and activate the NLRP3. High levels of Reactive Oxygen Species (ROS) cause the dissociation of TNXIP from thioredoxin (TRX) and binding to NLRP3.

Figure 3

Structure of some of the most common polyphenolic compounds. They contain one or more benzene rings joined to hydroxyl groups.