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Arthritis Rheumatol. 2015 Dec;67(12):3286-97. doi: 10.1002/art.39307.

Identification of Interleukin-1β-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease.

Author information

1
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.

Abstract

OBJECTIVE:

Spontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome-mediated interleukin-1β (IL-1β) processing and release and can induce rapid necrotic cell death. The cells that produce IL-1β in neonatal-onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL-1β release and cell death been completely elucidated.

METHODS:

Whole blood cells were stimulated with lipopolysaccharide (LPS) in the presence of cathepsin B and caspase 1 inhibitors, followed by ATP treatment. Supernatants were collected and incubated with IL-1β-capturing beads. Cells were fixed, permeabilized, and stained for a combination of cell surface and intracellular markers, and a novel flow cytometry bead-based assay was used to measure secreted IL-1β. LPS-stimulated cells were also evaluated using immunofluorescence microscopy.

RESULTS:

Monocytes characterized by CD14(high) -CD16(low) expression and intracellular CD83 were increased in NOMID patients and were responsible for the majority of IL-1β production in response to LPS stimulation. This population of monocytes also underwent a rapid death response with LPS alone that is temporally associated with IL-1β and ASC release and has characteristic features of pyronecrotic but not pyroptotic cell death. Inhibition of cell death reduced IL-1β production from NOMID patient cells. In addition, IL-1 triggered cell death in monocytes from NOMID patients.

CONCLUSION:

Our findings indicate that monocytes are the predominant IL-1β-producing cell population in the peripheral blood of NOMID patients. Furthermore, they suggest that IL-1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin-associated periodic syndromes.

PMID:
26245468
PMCID:
PMC5567735
DOI:
10.1002/art.39307
[Indexed for MEDLINE]
Free PMC Article

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