Abstract
Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.
Highlights
The mammalian immune system defends against internal and external threats using innate immunity and adaptive immunity (Neill et al, 2010)
In macrophage and animal models of uric acid accumulation, monosodium urate crystals activate the NLRP3 inflammasome, causing gout (Hari et al, 2014; Wang et al, 2014; Cleophas et al, 2015). These findings suggest that during the progression of many metabolic diseases, the accumulation of abnormal metabolic products activates the NLRP3 inflammasome
To provide an example of progress in this area, we focus below on studies of IFN therapy against multiple sclerosis in patients and EAE in mice, since type I IFN therapy has been used as a first-line or standard treatment of multiple sclerosis for 15 years (Inoue et al, 2012b)
Summary
The mammalian immune system defends against internal and external threats using innate immunity and adaptive immunity (Neill et al, 2010). A subsequent stimulus (shown as “Signal 2” in black) activates the NLRP3 inflammasome by facilitating the oligomerization of inactive NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1 This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of the mature IL-1β and IL-18. Ito et al (2015) showed that using ibrutinib to inhibit Bruton’s tyrosine kinase (BTK), an essential component of the NLRP3 inflammasome, reduced infarct volume, and neurological damage in a mouse model of cerebral ischemia/reperfusion injury It is reported by Hecker et al (2015) that activation of nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10 inhibited ATP-mediated IL-1β release by human and rat monocytes, helping protect them from collateral damage.
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