NLRP3 Inflammasome Signaling Platform as New Pharmacological Target for Metaflammation

Abstract

inflammatory response initiated by excess nutrients in metabolic cells.1 The inflammatory signaling conducted by the metabolic cell eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue.2 The high level of coordination of inflammatory and metabolic pathways is highlighted by the overlapping biology and function of macrophages and adipocytes in obesity. Preadipocytes under some conditions can exhibit phagocytic and antimicrobial properties and appear to even be able to differentiate into macrophages in the right environment, which suggests a potential immune role for preadipocytes. Furthermore, macrophages and adipocytes co-localize in white adipose tissue in obesity. Macrophages in adipose tissue are likely to contribute to the production of inflammatory mediators either alone or in concert with adipocytes, which suggests a potentially important influence of macrophages in promoting insulin resistance. Besides macrophages, obesity is associated
with aberrant expansion of other leukocytes (T-cells, B-cells, eosinophils, neutrophils and mast cells) in adipose tissue that contribute to chronic inflammation. In particular, the increased neutrophils lead to a rise of myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, in the damaged tissue during inflammation.3 Despite the role of meta-inflammation, in promoting metabolic diseases, including obesity and insulin resistance, is well known,4 from a therapeutic perspective, only limited experience is available regarding the inhibition of specific inflammatory pathways activated by the metabolic, biochemical and haemodynamic derangements
known to exist in CMD. Thus, effective treatments that halt or induce regression of meta-inflammation have potential to provide an immense clinical, social and economic benefit. Most recent evidences suggest a substantial role of the NLRP3 inflammasome in regulating meta-inflammation. The term “inflammasome” was coined by Tschopp and co-workers in 2002 to describe a high-molecular-weight complex present in the cytosol of stimulated immune cells that mediates the activation of inflammatory caspases.5 To date, five receptor proteins have been confirmed to assemble inflammasomes, including the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein (NLR) family members NLRP1, NLRP3 and NLRC4, as well as the proteins absent in melanoma 2 (AIM2) and pyrin. The bestcharacterized inflammasome is the NLRP3 inflammasome which interacts with an apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC), thus recruiting and activating caspase-1. Because caspase-1 is an IL-1β-converting enzyme, it mediates the processing of pro-IL-1β into mature IL-1β and the consequent release of IL-1β, thereby causing inflammation. Yet, the induction of IL-1β release requires the transcriptional induction of
pro-IL-1β. Thus, a system including pro-IL-1β induction and inflammasome-mediated IL-1β maturation seems necessary for the regulation of this inflammatory cytokine. The assembly of functional NLRP3 inflammasome requires two distinct steps, priming and activation, respectively at the transcriptional and post-transcriptional levels.