Abstract
The NLRC4 inflammasome assembles in response to detection of bacterial invasion, and NLRC4 activation leads to the production of IL-1β and IL-18 together with pyroptosis-mediated cell death. Missense activating mutations in NLRC4 cause autoinflammatory disorders whose symptoms are distinctly dependent on the site of mutation and other aspects of the genetic background. To determine the involvement of IL-1β and IL-18 in the inflammation induced by NLRC4 mutation, we depleted IL-1β, IL-18, or both cytokines in Nlrc4-transgenic mice in which mutant Nlrc4 is expressed under the MHC class II promoter (Nlrc4-H443P-Tg mice). The deletion of the Il1b or Il18 gene in Nlrc4-H443P-Tg mice reduced the neutrophil numbers in the spleen, and mice with deletion of both genes had an equivalent number of neutrophils compared to wild-type mice. Deletion of Il1b ameliorated but did not eliminate bone marrow hyperplasia, while mice deficient in Il18 showed no bone marrow hyperplasia. In contrast, tail bone deformity remained in the presence of Il18 deficiency, but Il1b deficiency completely abolished bone deformity. The decreased bone density in Nlrc4-H443P-Tg mice was counteracted by Il1b but not Il18 deficiency. Our results demonstrate the distinct effects of IL-1β and IL-18 on NLRC4-induced inflammation among tissues, which suggests that blockers for each cytokine should be utilized depending on the site of inflammation.
Highlights
Inflammasomes are composed of an assembler protein such as a nucleotide-binding domaincontaining proteins, a leucine-rich family protein, ASC and caspase-1, and inflammasome stimulation leads to the maturation and secretion of the IL-1b and IL-18 cytokines [1,2,3]
Data were collected on a FACS Canto II (BD Biosciences) flow cytometer and analyzed using FACS Diva (BD Biosciences) or FlowJo (Tree Star, OR, USA) software. Both IL-1b and IL-18 Are Required for Inflammation in Nlrc4-H443P-Tg Mice
The clinical phenotypes of cryopyrin-associated periodic fever syndrome (CAPS)-like syndrome caused by NLRC4 mutations are indistinguishable from those caused by NLRP3 mutations
Summary
Inflammasomes are composed of an assembler protein such as a nucleotide-binding domaincontaining proteins, a leucine-rich family protein, ASC and caspase-1, and inflammasome stimulation leads to the maturation and secretion of the IL-1b and IL-18 cytokines [1,2,3]. Inflammasome activation is induced by pathogen-associated molecular patterns as well as damage-associated molecular patterns. The activation of the inflammasome is accompanied by pyroptosis-mediated cell death, which causes burst secretion of IL-1b and IL-18 [1, 4]. Hyperactivation of inflammasomes causes several types of diseases called autoinflammatory disorders [5,6,7,8]. NLRP3 mutations were initially reported in cryopyrin-associated periodic fever syndrome (CAPS), which includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease [7].
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