Journal
JCI INSIGHT
Volume 6, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.147671
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Funding
- European Union (European Social Fund) [MIS-5000432, MIS-5033021]
- Research Account of the University of Crete
- European Research Council under the European Union [742390]
- Pancretan Health Association
- Swedish Research Council
- Swedish Rheumatism Association
- King Gustaf the Vth 80-year Foundation
- Swedish Society of Medicine
- European Research Council (ERC) [742390] Funding Source: European Research Council (ERC)
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IL-33, released during cell death, interacts with NETs in SLE patients, stimulating IFN-alpha production, and linking neutrophil activation, type I IFN production, and end-organ inflammation.
IL-33, a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells, eliciting potent inflammatory responses. We screened blood, skin, and kidney tissues from patients with systemic lupus erythematosus (SLE), a systemic autoimmune disease driven by unabated type I IFN production, and found increased amounts of extracellular IL-33 complexed with neutrophil extracellular traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging, and proteomic approaches, we show that SLE neutrophils, activated by disease immunocomplexes, release IL-33-decorated NETs that stimulate robust IFN-alpha synthesis by plasmacytoid DCs in a manner dependent on the IL-33 receptor ST2L. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, NETs derived from patients with SLE are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFN-alpha production elicited by NETs. We believe these data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production, and end-organ inflammation, with skin pathology mirroring that observed in the kidneys.
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