Dataset Information

Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18.

ABSTRACT: Recent research has led to novel findings in inflammasome biology and genetics that altered the diagnosis and management of patients with autoinflammatory syndromes caused by NLRP3-, Pyrin-, NLRP1-, and NLRC4-inflammasomes and spurred the development of novel treatments. The use of next-generation sequencing in clinical practice allows for rapid diagnosis and the detection of somatic mutations that cause autoinflammatory diseases. Clinical differences in patients with NLRP3, pyrin, and NLRP1 inflammasomopathies, and the constitutive elevation of unbound free serum IL-18 that predisposes to the development of macrophage activation syndrome (MAS) in patients with gain-of function mutations in NLRC4 led to the screening and the characterization of novel diseases presenting with constitutively elevated serum IL-18 levels, and start to unravel the biology of "high IL-18 states" that translate into the use of biomarkers that improve diagnosis and monitoring of disease activity and investigations of treatments that target IL-18 and IFN-gamma which promise to improve the management and outcome of these conditions. Lastly, advances in structural modeling by cryo-electron microscopy (cryo-EM) of gasdermin, and of NLRP3- and NLRC4-inflammasome assembly, and the characterization of post-translational modifications (PTM) that regulate inflammasome activation, coupled with high-throughput screening (HTS) of libraries of inflammasome-inhibiting compounds, promise a new generation of treatments for patients with inflammasome-mediated diseases.

SUBMITTER: Alehashemi S

PROVIDER: S-EPMC7477077 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18.

Alehashemi Sara S Goldbach-Mansky Raphaela R

Frontiers in immunology 20200825

Recent research has led to novel findings in inflammasome biology and genetics that altered the diagnosis and management of patients with autoinflammatory syndromes caused by NLRP3-, Pyrin-, NLRP1-, and NLRC4-inflammasomes and spurred the development of novel treatments. The use of next-generation sequencing in clinical practice allows for rapid diagnosis and the detection of somatic mutations that cause autoinflammatory diseases. Clinical differences in patients with NLRP3, pyrin, and NLRP1 inf ...[more]

PMID: 32983099

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Project description:Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1? (IL-1?), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1? in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis.Inflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain "sensor" proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1? (IL-1?) and IL-18. Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival.

Dataset Information

Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18.

Publications

Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18.

Similar Datasets

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