The autoinflammatory side of systemic sclerosis.

two highly pro-inflammatory interleukin (IL)-1 family cytokines, IL-1β and IL-18, under different danger signals with the purpose of host defense [4]. Several NOD-like receptor (NLR) family members assemble into the inflammasome complexes, among which NLRP3 remains the best studied and fully characterized inflammasome [5]. It consists of a basic NLR scaffold with a central nucleotide-binding and oligomerization (NACHT) domain, which is flanked by C-terminal leucine-rich repeats (LRRs) and N-terminal caspase recruitment and activation (CARD) or pyrin (PYD) domains, the adaptor molecule apoptosisassociated speck-like protein (ASC) and caspase-1. LRRs are believed to mediate the recognition of diverse ligands, whereas CARD and PYD domains are involved in the interaction with downstream signaling proteins [5]. Several pathogens and endogenous damage-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome. The activation of the NLRP3 inflammasome requires two separate steps. The first signal, which can derive from Toll-like receptors (TLRs), tumor necrosis factor receptor (TNFR) or interleukin 1 receptor (IL-1R) signaling, activates NF-κB for the transcription and translation of the immature proforms of IL-1β and IL-18. As a second step, enzymatic cleavage is needed to secrete these pro-inflammatory interleukins into the extracellular space. This requires the oligomerization of NLRP3 with ASC, which facilitates proteolytic cleavage of pro-caspase-1 to its active caspase-1 (also called IL-1β converting enzyme, ICE). In addition, once activated, caspase-1 induces its own secretion. Caspase-1 then cleaves the pro-cytokines to mature IL-1β and IL-18 that can be secreted. Although t he recent history of autoimmunity in general and rheumatological disease in particular has brought a significant number of major paradigm shifts, as represented by the wave of genome-wide association studies and new biotechnological treatments. The study of MartinezGodinez and colleagues [1] in this issue of IMAJ follows this direction and confirms the role of innate immunity and the inflammasome in systemic sclerosis (SSc). Indeed, the data presented support the NLRP3 over-expression in the SSc skin, as previously reported by others [2]. The present article, nevertheless, also identified a consequent increase in caspase-1, interleukin (IL)-1-β and IL-18, all downstream of the inflammasome activation. Interestingly, the inflammasome overexpression together with endothelin 1 (ET-1) over-expression has been found in both limited and diffuse SSc, suggesting a role in the disease-associated fibrosis of both the inflammasome and the vascular mediator ET-1. From a clinical standpoint, SSc remains a challenging disease because available treatments are largely unsatisfactory, particularly once fibrosis of the skin or the lungs is established. Similarly, there is an unmet need for molecules capable of counteracting the progression of inflammation and vascular damage that also characterize the disease [3]. Inflammasomes are large cytoplasmic macromolecular signaling complexes that control the proteolytic activation of the exact mechanism of second-signal NLRP3 activation is unknown, three distinct models have been proposed to account for NLRP3 activation: potassium efflux, the generation of reactive oxygen species, and phagolysosomal destabilization leading to cathepsin leakage into the cytosol [6]. Although NLRP3 inflammasome activation is critical to drive acute inflammation in the clearance of viral or bacterial infections, persistent activation of NLRP3 may be involved in the progression of several chronic fibrotic diseases, including pulmonary, kidney, heart and liver fibrotic diseases. Moreover, agents blocking inflammasomes, such as pirfenidone [7] and naclynamide [8], may be effective in counteracting fibrogenesis. As previously mentioned, the most studied products of the activated inflammasome are IL-1β and IL-18, which are structurally similar and are involved in autocrine and paracrine signaling targeting parasitic, bacterial or viral infections, or in systemic inflammation as a result of chronic disease. IL-1β is produced by many cell types, e.g., epithelial cells, fibroblasts, T cells, etc., in response to pathogens or damaged tissues. IL-1β can modulate the expression of its own mRNA via signaling mediated by the IL-1 receptor, and the signaling pathways involved induce increased p38 MAPK phosphorylation and NF-κB activity. IL-1β requires two signals for the protein secretion; the first signal is usually obtained via TLR or IL-1R signaling and up-regulates IL-1β gene transcription, and the second signal is obtained via inflammasome activation, cleaving caspase-1 leading to IL-1β maturation and secretion. The acute release of IL-1β into the peripheral blood in response to cellular stimuli up-regulates NLRP3 inflammasome, interleukin (IL)1β, IL-18, endothelin 1 (ET-1), systemic sclerosis (SSc)