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

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.

• Authors: Jehad H Edwan, Raphaela Goldbach-Mansky, Robert A Colbert
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 12 Pg. 3286-97 (Dec 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 26245468 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

• Antigens, CD
• CD83 antigen
• Carrier Proteins
• Caspase Inhibitors
• FCGR3B protein, human
• GPI-Linked Proteins
• IL1B protein, human
• Immunoglobulins
• Interleukin-1beta
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• Membrane Glycoproteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Receptors, IgG
• Cathepsin B

Topics

• Adolescent
• Adult
• Antigens, CD (immunology)
• Carrier Proteins (genetics)
• Caspase Inhibitors (pharmacology)
• Cathepsin B (antagonists & inhibitors)
• Cell Death (immunology)
• Child
• Child, Preschool
• Cryopyrin-Associated Periodic Syndromes (genetics, immunology)
• Female
• GPI-Linked Proteins (immunology)
• Humans
• Immunoglobulins (immunology)
• Infant
• Interleukin-1beta (immunology)
• Lipopolysaccharide Receptors (immunology)
• Lipopolysaccharides (pharmacology)
• Male
• Membrane Glycoproteins (immunology)
• Monocytes (drug effects, immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Necrosis (immunology)
• Pyroptosis
• Receptors, IgG (immunology)
• Young Adult