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.
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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)
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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
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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
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