NLRP3: A promising therapeutic target for autoimmune diseases
Introduction
Inflammasomes are a class of poly-protein complexes primarily composed of a sensor, an adaptor protein and an effector. Varieties of exogenous and endogenous stimuli, including microbes, nanoparticles, oxidized DNA, etc. can be recognized by the sensor- pattern-recognition receptors (PRRs), and subsequently trigger the downstream cascade reactions. Nucleotide-binding domain-(NOD) like receptors (NLRs) belong to the PRRs family [1]. To date, at least 8 subtypes of inflammasomes have been identified, among which NLR-associated ones are the most extensively studied, especially the nucleotide-binding oligomerization domain and leucine rich repeat pyrin 3 domain (NLRP3) [2]. Once activated, NLRP3 would oligomerize [3] and upregulate cellular synthesis and maturation of several pro-inflammatory cytokines or chemokines (e.g. IL-1β and IL-18) or trigger pyroptosis [4,5], thereby resulting in inflammation against environmental or host-derived antigens.
The immune system includes innate and acquired immunity, whose deficiency or inappropriate activation could lead to visceral or systemic dysfunctions. The innate immune system provides the first line of defense to recognize microbes or endogenous molecules via pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by host pattern recognition receptors (PRRs) [6]. As a crucial component of the innate immune system, the NLRP3 inflammasome acts an important role in host defense by recognizing viral infection and triggering autoimmune responses [[7], [8], [9], [10]]. Autoimmune disorders are a series of idiopathic diseases characterized by uncontrolled, chronic auto-inflammatory conditions. The most common autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), Sjögren's syndrome (SS), systemic sclerosis (SSc) [11], etc. Inflammasomes, a molecular platform activated upon signs of cellular “danger” to trigger innate immune defenses through the maturation of pro-inflammatory cytokines such as interleukin IL-1β [12], are closely knitted with autoimmune diseases [2]. Researchers expanded on the proposal via investigations into gene transcription or protein expression of the NLRP3 inflammasome signaling pathway in autoimmune diseases, and have gained remarkable findings, which strongly indicate that NLRP3 inflammasome complex may serve as a promising and novel therapeutic target for clinical treatment in inflammatory-related diseases [13].
In the present review, we will briefly discuss the immunological functions of NLRP3 and its role in autoimmune diseases, as well as their potential as therapeutic target for these diseases.
Section snippets
NLRP3 and its immunological functions
NLRP3 belongs to the NOD-like receptor family, which is the most extensively studied inflammasome. It is a protein of 1016 amino acids transcribed from the gene Cias1, which is located on the human chromosome 1q44 and contains 9 coding exons [14]. The architecture of NLRP3 is pyrin domain at the N-terminus (PYD), an array of 12 leucine-rich repeat domain (LRR) at the C-terminus and the intermediate nucleotide triphosphatase domain (NACTH) mediated oligomerization [14]. PYD allows homotypic
NLRP3 in autoimmune diseases
Autoimmune diseases are characterized by inappropriate immune response against the body's own cells, tissues or organs, which comprise of SLE, RA, SSc, IBD and other related diseases. Although the pathogenesis and etiology research on these diseases advancing, as well as continuous progress on treatment, the long-term prognoses are unsatisfactory for most patients [44,45]. Thus, there is an urgent need to explore novel, individualized therapeutic targets for clinic. These autoimmune diseases
NLRP3 as a promising therapeutic target for autoimmune diseases
Due to its paramount role in the pathogenesis of inflammation and autoimmunity, NLRP3 is expected to serve as a promising therapeutic agent for autoimmune diseases. Understanding the intrinsic mechanisms of NLRP3 in autoimmune diseases, together with the effort to discover and develop agents to specifically inhibit NLRP3 inflammasome activation [106], may pave the way for novel therapeutic approaches for autoimmune diseases.
In fact, treatment through blocking the activity of NLRP3 has yielded
Conclusion
The past decade has witnessed great advances in our understanding of molecular mechanisms underlying NLRP3 inflammasome activation and autoimmune diseases. Particularly, the regulation of IL-1β and IL-18 maturation by NLRP3 is beginning to be characterized in detail and many of these diseases can now be treated with antagonists of IL-1β and IL-18 or its receptor [98]. Coll et al. noted that targeting NLRP3 might present certain advantages over the use of biologic inhibitors of IL-1β [99].
Take-home messages
- 1.
NLRP3 inflammasome assemble upon activation of NLRP3, ASC and pro-caspase-1.
- 2.
The NLRP3 inflammasome promotes inflammation and pyroptotic cell death.
- 3.
NLRP3 exerts a key role in the development and pathogenesis of autoimmune disease.
- 4.
NLRP3 may serve as a promising therapeutic target for autoimmune disease.
Declarations of interest
None.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (81573222, 81473058).
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