Identification of Interleukin‐1β–Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal‐Onset Multisystem Inflammatory Disease. Issue 12 (25th November 2015)

• Record Type: Journal Article
• Authors: Edwan, Jehad H.; Goldbach‐Mansky, Raphaela; Colbert, Robert A.
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 12(2015)
• Page Start: 3286
• Page End: 3297
• Publication Date: 2015-11-25
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39307
• Languages: English
• ISSNs: 2326-5191

Abstract

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.