MCC950 in the treatment of NLRP3-mediated inflammatory diseases: Latest evidence and therapeutic outcomes

Highlights

• NLRP3 activation is involved in several inflammatory pathological states.

• MCC950 can inhibit NLRP3-dependent inflammation effectively.

• Human studies are needed to prove the effectiveness and reduction of inflammation by MCC950.

Abstract

Evidence suggests that various innate immune system components are involved in pathological inflammatory conditions. Among these components, the NLR family pyrin domain containing 3 (NLRP3) as an inflammasome can participate in destructive inflammatory responses by inducing the production of the active form of inflammatory cytokines. The NLRP3 could be involved in the pathogenesis of several inflammatory and autoimmune diseases such as type 2 diabetes mellitus, multiple sclerosis (MS), atherosclerosis, Alzheimer’s disease (AD), cryopyrin-associated periodic syndrome (CAPS), and infectious diseases. Therefore, the inhibition of NLRP3 can be a useful treatment option for inflammatory diseases. In this regard, MCC950, as a small molecule, is capable of inhibiting NLRP3 and, following inhibition of NLRP3, production of interleukin-1β (IL-1β) and IL-18 as pro-inflammatory cytokines reduced. Interestingly, the MCC950 can inhibit NLRP3 but no other inflammasomes such as NLRP1 and NLR family CARD domain containing 4 (NLRC4). This review summarized the structure and mechanism of action of MCC950 in the control of NLRP3-dependent inflammation and the role of MCC950 in the treatment of NLRP3-mediated inflammatory diseases based on the latest studies.

Introduction

Inflammasomes are cytosolic multi-protein involved in regulating innate immunity-mediated inflammation and pyroptosis, a type of programmed cell death. This protein complex in NLRP3 inflammasome consists of an absence in melanoma 2 (AIM2) or nucleotide oligomerization domain-like receptor (NLR) cytosolic sensor proteins, an apoptosis-associated speck-like protein containing a caspase recruitment domain, CARD (ASC) adaptor protein, and pro-caspase1 (Cas1) [1]. It has been known that physiological aberrations and viral/microbial patterns such as viral double-strand RNA (ds-RNA) could be sensed by AIM2-like receptors or nucleotide-binding domain and leucine-rich repeat receptors (NLRs), resulting in the initiation of the inflammasome complex assembling [2]. Following assembly of this complex and activation of the NLRP3 inflammasome, pro-Cas1 is converted to the active form of Cas1, leading to the cleavage of pro-IL-1β and pro-IL-18 precursors, creating a biologically active form of IL-1β and IL-18, which are involved in the inflammatory responses [3]. Furthermore, Cas1 is also responsible for cleavage of the N-terminal of gasdermin D (GSDMD), an executor of pyroptosis required for IL-1β and IL-18 secretion [4]. According to the available knowledge, ligation of lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) with their receptors trigger downstream adaptor molecule of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, producing of pro-IL-1β and pro-IL-18 [5]. The active form of IL-1β, as a potent inflammatory mediator, can play a role in several inflammation-related mechanisms, such as the transfer of innate immune cells to the site of infection as well as the transition of adaptive immune cells. On the other hand, the mature and active form of IL-18, which is the consequence of activation of NLRP3 inflammasome and Cas1, can also participate in inducing the production of interferon-gamma (IFN-γ), increasing the cytotoxicity of effector T cells as well as natural killer (NK) cells [6], [7]

Previous studies showed that the NLRP3 inflammasome plays a significant role in intestinal homeostasis and the induction of destructive inflammatory immune responses in several inflammatory disorders such as cardiovascular, autoimmune, central nervous system, metabolic, and renal diseases [8], [9], [10], [11], [12], [13]. Therefore, inhibition of NLRP3 can be a potential therapeutic approach for pathological inflammation-associated diseases [1], [14]. So far, numerous chemical and natural compounds have been introduced and studied to inhibit NLRP3. However, one of them, a diarylsulfonylurea-containing factor called MCC950, has been able to have satisfactory outcomes through selective inhibition of NLRP3 in treating human and animal models of inflammatory diseases [15], [16], [17], [18]. The mechanism of action of MCC950 has not yet been fully elucidated, but studies have shown that this compound can inhibit the activation of the inflammasome by inhibiting ASC oligomerization and binding to the NLRP3 NACHT domain’s Walker B motif [19]. Due to the importance of NLRP3-mediated inflammation and its destructive effects in several inflammatory diseases, this review has investigated the role of MCC950 as a selective and potential NLRP3 inhibitor and its outcomes in the treatment of inflammatory diseases.