Inflammasome biology, molecular pathology and therapeutic implications
Date
2018-02-18
Authors
Awad, Fawaz
Assrawi, Eman
Louvrier, Camille
Jumeau, Claire
Georgin-Lavialle, Sophie
Grateau, Gilles
Amselem, Serge
Giurgea, Irina
Karabina, Sonia-Athina
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier Inc.
Abstract
Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They
commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing
receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to forminflammasomes.
The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger
or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC
(apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting
in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates
the secretion of proinflammatory IL1β and IL18 cytokines and pyroptosis, a caspase-1-mediated form of
cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently,
non-canonical inflammasomes have been described, which directly sense intracellular pathogens through
caspase-4 and -5 in humans, leading to pyroptosis.
Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of
inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding
genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products
of inflammasome activation aswell as molecules that directly or indirectly inhibit inflammasome nucleation and
activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the
molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory
diseases and in selected common multifactorial inflammasome-mediated disorders.
Description
Keywords
Autoinflammation , Inflammasomes , Pyrin , Pyroptosis , Cytokines