Polimorphisms in Inflammasome Genes Are Involved in the Predisposition to Systemic Lupus Erythematosus

Pontillo, Alessandra; Girardelli, Martina; Kamada, Anselmo Jiro; Pancotto, João Alexandre Trés; Donadi, Eduardo Antônio; Crovella, Sérgio; Sandrin-Garcia, Paula

doi:10.3109/08916934.2011.637532

Cited by 156 publications

(98 citation statements)

References 25 publications

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“…The NLRP1/IL-1β axis has been reported to be associated with autoimmunity (20). NLRP1 polymorphisms are involved in the predisposition to systemic lupus erythematosus and rheumatoid arthritis (23,24). The results of the present study are concordant with previous studies and add novel findings to the current understanding of NLRP1 in arthritis.…”

Section: Discussionsupporting

confidence: 91%

P2X4 promotes interleukin-1β production in osteoarthritis via NLRP1

Fan

Zhao

Guo

et al. 2013

Molecular Medicine Reports

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Abstract. Interleukin-1β (IL-1β) has a significant role in osteoarthritis (OA). The purinergic receptor, P2X4, has previously been implicated in IL-1β secretion. The NLRP1 inflammasome mediates the production of IL-1β in inflammatory disorders. However, it is unknown whether P2X4 modulates NLRP1-mediated IL-1β release. In the present study, the correlation between the P2X4 receptor and NLRP1 was investigated in OA fibroblast-like synoviocytes (OAFLS). The expression of P2X4 and NLRP1 was detected in the OAFLS. The OAFLS were stimulated with P2X4 and the levels of IL-1β and matrix metalloproteinases (MMPs) were measured. To determine whether P2X4 is involved in NLRP1-triggered IL-1β production, NLRP1 small interfering RNA (siRNA) was used. In the OAFLS, a markedly higher expression of P2X4 and NLRP1 was revealed compared with that in the normal FLS. OAFLS stimulated by P2X4 resulted in concentration-dependent increases in the production of IL-1β, MMP-3 and MMP-9. Furthermore, P2X4-mediated IL-1β production was attenuated by the NLRP1 siRNA. The results of the present study indicate that P2X4 induced IL-1β, MMP-3 and MMP-9 production in the OAFLS. IL-1β induced by P2X4 is mediated via NLRP1. P2X4/NLRP1 may be important in the pathogenesis of OA and may represent a novel therapeutic target. IntroductionAs the most common form of arthritis, osteoarthritis (OA) is one of the most significant causes of disability in older adults (1), yet its exact etiology remains unknown (2). The diagnosis and evaluation of joint damage are predominantly based on clinical and radiological findings. With medical advances, molecular markers are likely to become promising indicators for evaluating local inflammation, joint alterations and cartilage damage (3).Fibroblast-like synoviocytes (FLS) have been accepted to be key in OA inflammation and joint destruction, primarily through their secretion of a wide range of proinflammatory mediators (4,5). In response to the proinflammatory cytokines, including interleukin-1β (IL-1β), the OAFLS produce chemokines that promote inflammation, neovascularization and cartilage degradation via activation of matrix-degrading enzymes, including matrix metalloproteinases (MMPs) (5). IL-1β is a multifunctional cytokine that contributes to the pathogenesis of OA (6). Investigations into the IL-1β signaling pathway led to the identification of novel potential drugs for the treatment of OA (7). However, current treatment with these drugs remains unsatisfactory, and further research is required to achieve the desired therapeutic goals (7).The inflammasome is a multi-protein complex that mediates the activation of caspase-1, which in turn produces the proinflammatory cytokines, . The human NLRP1 inflammasome was the first caspase-1-activating protein complex to be identified (9). Recent studies have indicated that NLRP3 is involved in the genetic predisposition and pathogenesis of crystal arthritis, including gouty and rheumatoid arthritis (10,11). Recently, a study has revealed that the expression of the P2X4...

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Section: Discussionsupporting

confidence: 91%

P2X4 promotes interleukin-1β production in osteoarthritis via NLRP1

Fan

Zhao

Guo

et al. 2013

Molecular Medicine Reports

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“…The clearest connection between autoimmunity and the inflammasome is in the case of NLRP1. SNPs in NLRP1 have been linked to vitiligo and vitiligo-associated Addison's disease (Jin et al 2007), Type 1 diabetes (Magitta et al 2009), systemic lupus erythematosus (Pontillo et al 2012b), Kawasaki disease (Onoyama et al 2012), Addison's disease (Magitta et al 2009;Zurawek et al 2010), celiac disease (Pontillo et al 2011), rheumatoid arthritis (Sui et al 2012), systemic sclerosis (Dieude et al 2011), and autoimmune thyroid disease (Alkhateeb et al 2013). Despite these findings, confirmation of the role of NLRP1 in autoimmunity in mice has remained challenging because mice have three orthologs of NLRP1, whereas humans have only one.…”

Section: Metabolic Syndrome and Type 2 Diabetesmentioning

confidence: 99%

Inflammasomes

de Zoete,

Palm,

Zhu

et al. 2014

Cold Spring Harbor Perspectives in Biology

321

231

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“…Concomitant occurrence of multiple autoimmune diseases in some patients is well known (3)(4)(5) and results from shared genetic and perhaps environmental risk factors among these different diseases (6)(7)(8). Polymorphisms of the nuclear localization leucine-rich-repeat protein 1 (NLRP1) gene encoding the NACHT (NAIP, CIITA, HET-E, TP1) domain of NLRP1 have been associated with a number of autoimmune diseases, including vitiligo (9, 10), Addison disease (11,12), type 1 diabetes (11), celiac disease (13), systemic lupus erythematosus (14), rheumatoid arthritis (15), systemic sclerosis (16), Kawasaki disease (17), as well as steroid responsiveness in inflammatory bowel disease (18), although the specific biological mechanism underlying these genetic associations remains unknown.…”

mentioning

confidence: 99%

NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

Levandowski

Mailloux

Ferrara

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

200

132

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Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a key regulator of the innate immune system, particularly in the skin where, in response to molecular triggers such as pathogenassociated or damage-associated molecular patterns, the NLRP1 inflammasome promotes caspase-1-dependent processing of bioactive interleukin-1β (IL-1β), resulting in IL-1β secretion and downstream inflammatory responses. NLRP1 is genetically associated with risk of several autoimmune diseases including generalized vitiligo, Addison disease, type 1 diabetes, rheumatoid arthritis, and others. Here we identify a repertoire of variation in NLRP1 by deep DNA resequencing. Predicted functional variations in NLRP1 reside in several common high-risk haplotypes that differ from the reference by multiple nonsynonymous substitutions. The haplotypes that are high risk for disease share two substitutions, L155H and M1184V, and are inherited largely intact due to extensive linkage disequilibrium across the region. Functionally, we found that peripheral blood monocytes from healthy subjects homozygous for the predominant high-risk haplotype 2A processed significantly greater (P < 0.0001) amounts of the IL-1β precursor to mature bioactive IL-1β under basal (resting) conditions and in response to Toll-like receptor (TLR) agonists (TLR2 and TLR4) compared with monocytes from subjects homozygous for the reference haplotype 1. The increase in basal release was 1.8-fold greater in haplotype 2A monocytes, and these differences between the two haplotypes were consistently observed three times over a 3-mo period; no differences were observed for IL-1α or TNFα. NLRP1 RNA and protein levels were not altered by the predominant high-risk haplotype, indicating that altered function of the corresponding multivariant NLRP1 polypeptide predisposes to autoimmune diseases by activation of the NLRP1 inflammasome.cytokine | DNA sequencing | interleukin-1beta

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Polimorphisms in Inflammasome Genes Are Involved in the Predisposition to Systemic Lupus Erythematosus

Cited by 156 publications

References 25 publications

P2X4 promotes interleukin-1β production in osteoarthritis via NLRP1

P2X4 promotes interleukin-1β production in osteoarthritis via NLRP1

Inflammasomes

NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

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