Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment

Mathews, Rebeccah J.; Robinson, Jim; Battellino, M.; Wong, Chi Huey; Taylor, John; Eyre, Steve; Churchman, Sarah M.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme L; Barton, Anne; Plant, Darren; Savic, Sinisa; Cook, Graham P.; Sarzi-Puttini, Piercarlo; Emery, Paul; Barrett, Jennifer; Morgan, Ann W; McDermott, Michael F.

doi:10.1136/annrheumdis-2013-203276

Cited by 183 publications

(148 citation statements)

References 41 publications

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“…CARD8 was originally described as a member of the NLRP3 inflammasome (114) but this has not been confirmed in subsequent studies. However, the link between CARD8 and NLRP3 is supported by the fact that polymorphisms in CARD8 together with NLRP3 polymorphisms have been implicated in several diseases including Crohn's disease, psoriasis and rheumatoid arthritis (284,(302)(303)(304). Lastly, there are also regulatory proteins that can promote inflammasome assembly or are required for NLRP3 activation.…”

Section: Regulation Of the Inflammasome And Il-1β Productionmentioning

confidence: 98%

“…Genetic alterations in NLRP3 are associated with increased susceptibility to a number of inflammatory diseases including gout, psoriasis, rheumatoid arthritis and Crohn's disease (283)(284)(285)(286). However, the association between NLRP3 alterations and inflammatory disease caused by excessive IL-1β is strongest in a group of autoinflammatory disorders known as cryopyrin-associated periodic syndromes (CAPS) and includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular syndrome.…”

Section: Genetic Alterations Of the Inflammasomementioning

confidence: 99%

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Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Eklund¹

2013

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Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis. To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active...

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Section: Regulation Of the Inflammasome And Il-1β Productionmentioning

confidence: 98%

Section: Genetic Alterations Of the Inflammasomementioning

confidence: 99%

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Eklund¹

2013

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“…One of the latest studies published found solid evidence ofmodulation ofthe NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF (2).…”

mentioning

confidence: 99%

“…It is believed, that this cytokine superactivation, or deregulation, has an impact on the different areas of the so-called inflammasome, but also of the extrinsic apoptotic pathway (2,3).…”

mentioning

confidence: 99%

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Carcinoma Cuniculatum in Course of Etanercept: Blocking Autoimmunity but Propagation of Carcinogenesis?

Tchernev

Guarneri

Bevelacqua

et al. 2014

Int J Immunopathol Pharmacol

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Carcinoma cuniculatum (CC) or verrucous squamous cell carcinoma is a rare variant of squamous cell carcinoma with low incidence of metastasis. It mainly affects men during the fifth-sixth decade of life, arising mostly on the weight-bearing surface of the foot, but it can also be found in other body areas. The favorable effects on the psoriatic, rheumatoid, juvenile polyarthritis as well as the ankylosing spondylitis after the application of Tumour Necrosis Factor (TNF)-alpha inhibitors, like etanercept, presume the availability of similarity between the etiopathogenetic mechanisms which are responsible for the generation of the inflammatory cascade. According to the latest studies, the sensitivity of the patients to TNF-alpha inhibitors could be genetically determined and may also be due to certain genetic polymorphisms of the NLP3 and CARD8 zones of the inflammasome. The blocking of the inflammatory reaction within the borderlines of the psoriatic arthritis could also be accepted as something of a “double edged sword”. There is a growing volume of literary data which informs us of the clinical manifestation, not only of skin, but also of other types of tumors after the application of TNF-alpha inhibitors. This inevitably generates the hypothesis that within a certain group of patients the TNF-alpha inhibitors have some additional, and currently obscure, effects on presumably key regulatory proteins of the so-called extrinsic apoptotic pathway. Other proteins of the human inflammasome could be also implicated in the regulation of the programmed cell death and the carcinogenesis - there are speculations, that the adapter protein, ASC/TMS1, could be one of these. The present study describes the case of a patient who developed a rare form of skin tumor - epithelioma cuniculatum - whilst undergoing etanercept therapy for psoriatic arthritis. Under discussion are the possible critical connections in the complex regulatory “networks” of the inflammatory processes, the programmed cell death (apoptosis) and the carcinogenesis which, in the near or distant future, could become the objects of a targeted therapy.

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ASPS Exhibits Anti‐Rheumatic Effects by Reprogramming Gut Microbiota and Increasing Serum γ‐Glutamylcysteine Level

Liu

Zhang

et al. 2022

Advanced Science

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Rheumatoid arthritis (RA) is an essential cause of labor loss and disability for people worldwide. Acanthopanax senticosus polysaccharide (ASPS) is one of the most important active components from A. senticosus , which exhibits various pharmacological activities such as antioxidation and immunomodulation. However, no studies have reported the application of ASPS in treating RA. This study aims to investigate the therapeutic effect of ASPS on RA and reveal its underlying mechanism. The potential therapeutic effect of ASPS against RA is initially verified in this study using the collagen‐induced arthritis model. Moreover, the protective benefits of ASPS are transmitted through the fecal microbiota and blocked by simultaneous antibiotic cocktail treatment, indicating that gut microbiota may be correlated with ASPS. The 16S rRNA sequencing using feces samples and untargeted UPLC‐MS metabolomics using serum samples further reveal that ASPS reprograms the arthritic progression triggered dysbiosis, enhances the expression of γ ‐glutamylcysteine (GGC) synthetase, and enriches the serum concentration of GGC. Furthermore, metabolites GGC is found to be able to effectively interrupt NLRP3 inflammasome activation via inhibiting ASC nucleation and therefore attenuate inflammatory arthritis. Taken together, this work highlights ASPS's therapeutic potential against RA, which mainly exhibits its effects via modulating gut microbiota and regulating GGC production.

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Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment

Cited by 183 publications

References 41 publications

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

Carcinoma Cuniculatum in Course of Etanercept: Blocking Autoimmunity but Propagation of Carcinogenesis?

ASPS Exhibits Anti‐Rheumatic Effects by Reprogramming Gut Microbiota and Increasing Serum γ‐Glutamylcysteine Level

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