Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Saito, Megumu K.; Nishikomori, Ryuta; Kambe, Naotomo; Fujisawa, Akihiro; Tanizaki, Hideaki; Takeichi, Kyoko; Imagawa, Tomoyuki; Iehara, Tomoko; Takada, Hidetoshi; Matsubayashi, Tadashi; Tanaka, Hiroshi; Kawashima, Hisashi; Kawakami, Kiyoshi; Kagami, Shinji; Okafuji, Ikuo; Yoshioka, Takakazu; Adachi, Souichi; Heike, Toshio; Miyachi, Yoshiki; Nakahata, Tatsutoshi

doi:10.1182/blood-2007-06-094201

Cited by 133 publications

(115 citation statements)

References 53 publications

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“…Given our present findings, the failure to increase IL-1β secretion in response to ATP is likely due to exhaustion of the antioxidant systems and the consequent impossibility of mounting a redox response to P2X7 receptor triggering. The breakdown of the antioxidant response also might be the cause of the premature death observed in CAPS monocytes (25). But in our patients, an increase in cell death compared with controls was detected only at later times after LPS exposure, ruling out the possibility that the early attainment of a plateau and cessation of IL-1β secretion is due to cell death.…”

Section: Discussioncontrasting

confidence: 44%

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi¹,

Carta²,

Delfino³

et al. 2010

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

126

159

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In healthy monocytes, Toll-like receptor (TLR) engagement induces production of reactive oxygen species (ROS), followed by an antioxidant response involved in IL-1β processing and secretion. Markers of the antioxidant response include intracellular thioredoxin and extracellular release of reduced cysteine. Cryopyrinassociated periodic syndromes (CAPS) are autoinflammatory diseases in which Nod-like receptor family pyrin domain-containing 3 (NLRP3) gene mutations lead to increased IL-1β secretion. We show in a large cohort of patients that IL-1β secretion by CAPS monocytes is much faster than that by healthy monocytes. This accelerated kinetics is caused by alterations in the basal redox state, as well as in the redox response to TLR triggering displayed by CAPS monocytes. Indeed, unstimulated CAPS monocytes are under a mild oxidative stress, with elevated levels of both ROS and antioxidants. The redox response to LPS is quickened, with early generation of the reducing conditions favoring IL-1β processing and secretion, and then rapidly exhausted. Therefore, secretion of IL-1β is accelerated, but reaches a plateau much earlier than in healthy controls. Pharmacologic inhibition of the redox response hinders IL-1β release, confirming the functional link between redox impairment and altered kinetics of secretion. Monocytes from patients with juvenile idiopathic arthritis display normal kinetics of redox response and IL-1β secretion, excluding a role of chronic inflammation in the alterations observed in CAPS. We conclude that preexisting redox alterations distinct from CAPS monocytes anticipate the pathogen-associated molecular pattern molecule-induced generation of the reducing environment favorable to inflammasome activation and IL-1β secretion.antioxidant response | inflammasome | reactive oxygen species | thioredoxin | autoinflammatory diseases

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Section: Discussioncontrasting

confidence: 44%

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi¹,

Carta²,

Delfino³

et al. 2010

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

126

159

View full text Add to dashboard Cite

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“…LPS-treated monocytes expressing the Y570C mutation showed an increased necrotic-like cell death associated with lysosomal leakage and other cellular metabolic alterations. 80,81 Moreover, monocytes transfected with Y570C exhibited higher NF-kB activity compared to healthy controls. 82,83 A second important aspect is that some CINCA patients with milder symptoms apparently lack NLRP3 mutations but carry a latent lowlevel mosaicism.…”

Section: Genetics Of Inflammasomes In Autoinflammatory Diseasesmentioning

confidence: 98%

“…This implies that some missense mutations in the NLRP3 gene can exert a dominant phenotype leading to CAPS even when NLRP3 is expressed by less than 25% of the cells in mosaic patients. 81,84 This could be due to the positive feedback loop sustained by the IL-1/IL-1R axis.…”

Section: Genetics Of Inflammasomes In Autoinflammatory Diseasesmentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

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Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1b activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

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“…There is no difference in clinical phenotype in patients with and those "without" mutations except for a difference in IL-1 release from peripheral blood mononuclear cells. (Gattorno et al) Recent reports have shown the presence of somatic mosaicism in such "mutation-negative" patients [19,20].…”

Section: New Perspectives On the Pathogenesis Of Caps/nomidmentioning

confidence: 99%

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

2011

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Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin-(NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the "NLRP3 inflammasome," an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1-blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1-blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient's disease severity and organ manifestations.

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Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Cited by 133 publications

References 53 publications

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

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