NETs decorated with bioactive IL-33 infiltrate inflamed tissues and induce IFN-α production in patients with SLE.

Spiros Georgakis, Katerina Gkirtzimanaki, Garyfalia Papadaki, Hariklia Gakiopoulou, Elias Drakos, Maija-Leena Eloranta, Manousos Makridakis, Georgia Kontostathi, Jerome Zoidakis, Eirini Baira, Lars Rönnblom, Dimitrios T Boumpas, Prodromos Sidiropoulos, Panayotis Verginis, George Bertsias

Journal: JCI insight 2022;6(21):e147671

PMID: 34554930

Free Full Text on American Society for Clinical Investigation View on PubMed

Abstract

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-α 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-α 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.

Address: Laboratory of Rheumatology, Autoimmunity and Inflammation, University of Crete, Medical School, Iraklio, Greece.; Infections and Immunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), Iraklio, Greece.; 1st Department of Pathology, National and Kapodistrian University of Athens Medical School, Athens, Greece.; Department of Pathology, University of Crete, Medical School, Iraklio, Greece.; Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Biotechnology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.; Laboratory of Toxicological Assessment of Pesticides, Scientific Directorate of Pesticides Assessment and Phytopharmacy, Benaki Phytopathological Institute, Athens, Greece.; Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece.; Joint Rheumatology Program and 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.; Infections and Immunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas (FORTH), Iraklio, Greece.; Laboratory of Immune Regulation and Tolerance, University of Crete, Medical School, Iraklio, Greece.

DOI: 10.1172/jci.insight.147671

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MeSH Terms: Case-Control Studies, Dendritic Cells, Extracellular Traps, Humans, Interferon-alpha, Interleukin-33, Lupus Erythematosus, Systemic