Overview

Dermatomyositis (DM) and polymyositis (PM) are common inflammatory myopathies, which are characterized by subacute or chronic progressive muscle weakness, myalgia, and multi-organ involvement.It is commonly thought that DM is a complement-mediated microangiopathy and PM is T-cell mediated myopathy. In DM, the complement C5b9 membrane attack complex is activated and deposited on endothelial cells, leading to necrosis, ischemia, and muscle fiber destruction resembling microinfarcts. The cluster of differentiation (CD)8⁻ major histocompatibility complex (MHC) Class I complex is characteristic of PM, and the perforin released by CD8 cells causes muscle fiber necrosis.^[Both PM and DM are potentially treatable myopathies, and glucocorticoids form the basis of treatment. However, the treatment efficiency is heterogeneous between different patients. The immunopathogenic mechanisms behind these diseases remain poorly understood and require further study. (1)

Inflammasome

The inflammasome is a large molecular platform that triggers the activation of inflammatory caspases and the processing of pro-interleukin-1β (pro-IL-1β) and pro-IL-18. The inflammasome, which was first described in 2002, was thought to act as a signaling platform that can respond to infections, as well as endogenous cellular stress products. It was also thought that it played a vital role in innate immunity. (2)

NOD-like receptor family

Among the kinds of inflammasomes, the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied inflammasome, which consists of the NLR family member NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the effector protein pro-caspase-1. After responding to the stimuli of microbial activators  or endogenous danger signals, such as Adenosine Triphosphate (ATP), uric acid crystals, and β-amyloid, the NLRP3 inflammasome assembled through the ASC domain autoclaves the pro-caspase-1 into active caspase-1, which in turn cleaves the pro-forms of the cytokines IL-1β and IL-18 to their active and secreted forms.The proinflammatory cytokines, IL-1β and IL-18, will regulate the immune response by increasing the expression of adhesion molecules on endothelial cells, enabling the transmigration of leukocytes, and by stimulating antibody production.(3,4)

Review

According to previous studies, DM/PM is generally considered autoimmune muscle disorders. However, the underlying immunopathogenic mechanisms of DM/PM remain poorly understood. According to previous research, the immune response of DM is thought to target the endothelium of capillaries and small blood vessels, leading to the activation of the complement and deposition of C5b9 membrane attack complexes, resulting in the depletion of capillaries and muscle ischemia. Meanwhile, the pathogenesis of PM is mainly mediated by toxic CD8⁺ T-cells. The CD8/MHC-I complex is characteristic muscle pathology for PM. CD8⁺ cells surround and invade nonnecrotic muscle fibers, which express MHC Class I molecules and are thought to cause perforin-mediated cytotoxic injury. No matter what kind of immune cells infiltrate the muscle tissue, it is a process that is heavily dependent upon the presence of multiple cytokines.The cellular sources of cytokines are immune cells, endothelial cells, and muscle cells, and their interrelations have the potential to amplify inflammatory responses. Recent studies have demonstrated that the overexpression of tumor necrosis factor (TNF), interferon (IFN), and IL are key mediators in the pathogenesis of DM/PM.^[ TNF-α is believed to be an important regulator of the inflammation associated with DM/PM. A previous study indicated that TNF-α mRNA was upregulated in DM (X12) and PM (X26).^[ In Greenberg's study, gene expression microarray has shown that IFN-α/β-inducible gene and protein expression might be an important part of the pathogenesis of DM. While in the IL family, IL-1β and IL-18 regulate the immune response in DM/PM. Baird also found that there was a significant upregulation of IL-1β compared to IL-1α. In addition, two studies conducted by Tucci et al. suggested that the deregulated IL-18/IL-18R pathway might be pathogenetic in inflammatory myopathies and the measurement of IL-18 might be predictive of the disease activity. In our study, the significant elevations of serum IL-1β/IL-18 and mRNA expression of IL-1β/IL-18 in muscle samples are observed in the DM/PM patient group, which indicate the implication of IL-1β/IL-18 in the pathogenesis of DM/PM. The next aim is to find the source of IL-1β/IL-18. (5,6)

IL-1β and IL-18 exist in the cytoplasm as the proinflammatory cytokines, pro-IL1β and pro-IL18, which will be secreted and functional only after being cleaved by caspase-1. In addition, the NLRP3 inflammasome is a key factor in this process. This inflammasome is an intracellular macromolecular complex that serves as a platform for the activation of proinflammatory caspase-1, which in turn cleaves IL-1β and IL-18 from their preforms. Diverse molecular entities, including bacteria, viruses, purified microbial products, components of dying cells, small molecule immune activators, and crystalline or aggregated materials can activate NLRP3.^[ When activated, NLPR3 senses the ligand via its C-terminal leucine-rich repeat domain and undergoes an ATP-dependent self-oligomerization mediated by an intermediate nucleotide binding and oligomerization domain (NACHT). Then, a homotypic interaction between the N-terminal pyrin domain of NLRP3 and ASC, and subsequently between the caspase activation and recruitment domain of the ASC and pro-caspase-1, will recruit pro-caspase-1 to the high molecular weight complex, leading to its auto-cleavage and activation. Recent studies have demonstrated that NLRP3 inflammasome is involved in the pathogenesis of multiple autoimmune diseases. One study indicated that in DM/PM patients, the high expression of the NLRP3 inflammasome in muscle tissue led to high expression of activated caspase-1, which in turn caused the upregulation of IL-1β and IL-18 and enhanced cellular immunity. In contrast, we did not find significant differences in NLRP3 and caspase-1 expression for the DM/PM patients and the controls (data not shown), which might indicate that the NLRP3 inflammasome is implicated in the local muscle inflammation in DM/PM, and the released IL-1β/IL-18 could exacerbate disease progression. (6)

Activation

The cause of NLRP3 inflammasome activation in DM/PM is poorly understood until now. Cassel and Sutterwala  indicated that cell disruption leads to endogenous NLRP3 inflammasome activation. Following cellular disruption, the inflammasome can spontaneously form and acquire the ability to process pro-IL1β into its mature form. In addition, muscle fiber necrosis might release high mobility group box-1, ATP, and hyaluronic acid, which are damage-associated molecular patterns and might be activators of the NLRP3 inflammasome. Furthermore, in one of the three NLRP3 activation models generally supported in the current literature, the release of cathepsin B is somehow sensed by NLRP3 and inflammasome activation is triggered. While the upregulation of cathepsin B is related to PM disease activity and the inhibition of cathepsin B showed protective effects in a guinea pig model,^[ the relation of NLRP3 and cathepsin B in DM/PM needs to be studied. (7,8,9)
 

Relevance

To be noted, there was great heterogeneity of the patients recruited in this review that some received treatment while some did not. This would cause great variation of the result. Moreover, we need to do deep research on animal model to explain the role of NLRP3 inflammasome in the pathogenesis more clearly.

In conclusion, the NLRP3 inflammasome plays a key role in the development of DM/PM.  And further investigations needs to be performed.

Footnotes

1. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010) PubMed-Article
2. Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–33 (2010) .PubMed-Article
3. Kastner, D. Autoinflammatory disease reloaded: a clinical perspective. Cell 140, 784–790 (2010) .PubMed-Article
4. Franchi, L.,. Inflammasomes as microbial sensors. Eur. J. Immunol. 40, 611–615 (2010) .PubMed-Article
5. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008) .PubMed-Article
6. Latz, E. NOX-free inflammasome activation. Blood 116, 1393–1394 (2010)-PubMed-Article
7. Brookes, P. S.Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am. J. Physiol. Cell Physiol. 287, C817–C833 (2004) .PubMed-Article
8. Li, N. et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J. Biol. Chem. 278, 8516–8525 (2003) .PubMed-Article
9. Goldman, S. Autophagy and the degradation of mitochondria. Mitochondrion 10, 309–315 (2010)