CAPS and NLRP3

Booshehri, Laela M.; Hoffman, Hal M.

doi:10.1007/s10875-019-00638-z

Cited by 192 publications

(160 citation statements)

References 82 publications

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“…CAPS are inherited autoinflammatory disorders characterized by systemic inflammation with fever often presenting with skin rashes and central nervous system inflammation. While arthralgia is common in patients with CAPS, arthritis is less frequent . Inflammation in CAPS is caused by gain‐of‐function mutations in NLRP3, leading to aberrant inflammasome activation and direct initiation of an inflammatory cascade .…”

Section: Nlrs Function As Sensors Of Pathogens and Cellular Perturbatmentioning

confidence: 99%

“…While arthralgia is common in patients with CAPS, arthritis is less frequent. 19 Inflammation in CAPS is caused by gain-of-function mutations in NLRP3, leading to aberrant inflammasome activation and direct initiation of an inflammatory cascade. 20 These findings demonstrated that inflammasome activation per se was sufficient to initiate a full-blown systemic inflammation in humans.…”

Section: Nlr S Fun C Ti On a S S En Sor S Of Pathog En S And Cellulmentioning

confidence: 99%

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Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

126

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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Section: Nlrs Function As Sensors Of Pathogens and Cellular Perturbatmentioning

confidence: 99%

Section: Nlr S Fun C Ti On a S S En Sor S Of Pathog En S And Cellulmentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

126

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“…These hereditary cryopyrin-associated periodic syndromes (CAPS) are typified by chronic inflammatory symptomology caused by point mutations in the NLR family gene NLRP3, resulting in the production of a hyper-active NLRP3 protein [12,13].…”

Section: Introductionmentioning

confidence: 99%

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Herrmann

Anderson

Martinez

et al. 2020

Preprint

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Background An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer’s and Parkinson’s disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyper-activating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopamine neuron specific Slc6a3 promoter. Methods We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3A350V and Nlrp3L351P inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopamine neuron specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month old animals. Results We observed progressive and significant deficits in motor function in animals expressing Nlrp3L351P, compared with animals expressing Nlrp3WT and Nlrp3A350V. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3L351P compared with Nlrp3WT and Nlrp3A350V. Further analysis of Nlrp3L351P striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes. Conclusions Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the Nlrp3 locus is active in dopaminergic neurons in aging mice, and that the hyperactive Nlrp3L351P allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.

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“…NLR contains a pyrin domain such as NLRP3 and/or caspase activation domains (CARD), which promotes its self-assembly, some NLRs form multiprotein complexes called inflammasomes, which protect the cell from injuries as well as regulate homeostasis. The gain-of-function mutations in NLRP3 cause hyperactivation of cryopyrininflammasome and thus cause disease manifestations [31] [32].…”

Section: Cryopyrinopathymentioning

confidence: 99%

Phenocopies: Mimics of Inborn Errors of Immunity

Alonso-Bello¹,

Espinosa‐Padilla²,

Temix-Delfin³

et al. 2020

OALib

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A phenocopy is defined as a clinical non-inherited phenotype in an individual, with environmental induction, which is identical to the genetically determined phenotype of another. Until February 2017, the IUIS (International Union of Immunological Societies) reported in its classification 354 innate immunity errors and a final group (classification table IX) with conditions that are not part of the innate alterations and are called phenocopies. These are classified into two types, the associated with somatic mutations and those associated with auto-antibodies. The phenotypes that occur by any of the mechanisms mentioned are complex and varied. It is necessary to know the clinical manifestations of the pathologies classified in this group to enrich the possible differential diagnoses in individuals with suspected immunodeficiency.

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CAPS and NLRP3

Cited by 192 publications

References 82 publications

Inflammasomes contributing to inflammation in arthritis

Inflammasomes contributing to inflammation in arthritis

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

Phenocopies: Mimics of Inborn Errors of Immunity

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