The Role of NLRP3, a Star of Excellence in Myeloproliferative Neoplasms

Abstract

Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune diseases. NLRP3 belongs to the pattern recognition receptors (PRRs) family, expressed in numerous immune cells, and it plays its primary function in myeloid cells. NLRP3 has a crucial role in myeloproliferative neoplasms (MPNs), considered to be the diseases best studied in the inflammasome context. The investigation of the NLRP3 inflammasome complex is a new horizon to explore, and inhibiting IL-1β or NLRP3 could be a helpful cancer-related therapeutic strategy to improve the existing protocols.

Keywords: inflammasome; myeloproliferative neoplasms; nucleotide-binding domain (NOD)-like receptor protein 3.

Figure 1

NLRP3 protein is composed of a leucine-rich repeat (LRR) domain at the C-terminus, a nucleotide-binding oligomerization (NOD or NACHT) domain in the middle and a pyrin domain (PYD) at the N-terminus [49]. The central NACHT domain provides the ATPase activity necessary for the NLRP3 activation and inflammasome formation [77]. Numerous studies revealed that the NLRP3 activity is likewise controlled by the various post-translational modifications [78] and many NLRP3-interacting proteins [79]. The NLRP3 inflammasome complex is composed of caspase-1 and an adaptor protein called apoptosis-associated speck-like protein (ASC) [47]. The ASC and pro-caspase-1 both consist of caspase activation and recruitment domains (CARD) at the C-terminus. The ASC is composed of a pyrin domain at the N-terminus while pro-caspase-1 has a casp-1 domain. By recruiting the ASC through PYD–PYD contact, the NLRP3–PYD domain is necessary to develop the active inflammasome [80]. The inactive form of this protein complex is found in the cytosol and the endoplasmic reticulum [81]. As soon as it is activated, it spreads to the mitochondria, transforming into an aggregate composed of multiple NLRP3 molecules, called “speck complexes”, each containing the NLRP3 protein, ASC, and pro-caspase 1 [65,82,83]. The ASC enables the association with the PRR component and CARD—the interaction motifs that mediate the formation of larger protein complexes—facilitating the binding between pro-caspase-1 and the PRR–ASC complex [79].

Figure 2

MPN is accelerated by the overactive inflammatory STAT and NF-κB1 signaling pathways. The MPN patients’ BM cells with the JAK2V617F mutation showed a high expression of the NLRP3, NF-κB1, IL-1β, IL-18, and CARD8 genes. The NLRP3 inflammasome priming step was activated by the PAMPs, LPS and cytokines through the NF-κB1 pathway. In the nucleus, this molecule promoted the transcription of NLRP3, IL-1β and IL-18. The NF-κB-94 ins/del ATGG (rs28362491) polymorphism was related to the enhancement of NF-κB1 and the NLRP3 expression. The inflammasome assembly (activation step) was brought on by a Ca2+ efflux and the PAMPs and DAMPs through a K+ efflux increase. NLRP3 combined with the ASC and caspase-1 proteins to form the spike complex. The spike cleaved pro-IL-1β, pro-IL-18 and GSDMD into their active form. GSDMD pore forming, along with the K+ efflux and IL-1β protein, gave rise to pyroptosis. The KrasG12D mutation enhanced the NLRP3/IL-1β axis and also increased the NLRP3 activation, triggering the RAC1/ROS signaling. Normally, the miR-146a protein negatively regulates the innate immunological and inflammatory responses. Otherwise, the expression of the miR-146a rs2431697 TT genotype was frequently found in MPNs patients and was linked to an elevated expression of NLRP3, NF-κB1, and IL-1β inflammatory genes. NLRP3: nucleotide-binding domain-like receptor protein 3; EPO: erythropoietin; TPO: thrombopoietin; PAMPs: pathogen-associated molecular patterns; DAMPs: danger-associated molecular patterns; LPS: lipopolysaccharide; TLR: toll-like receptor; GSDMD: gasdermin-D.