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

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

doi:10.1172/jci.insight.147671

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.

Highlights

Systemic Lupus Erythematosus (SLE) is the prototype systemic autoimmune disease characterized by dysregulated innate and adaptive immunity leading to generation of autoantibodies and formation of immune complexes (ICs) deposited to afflicted tissues such as the skin and kidneys [1]
IL-33 decorated neutrophil-derived chromatin extracellular traps (NETs) are detected in inflamed tissues of patients with active SLE We focused on the role of IL-33, a nuclear alarmin released during cell death, in SLE
Serum IL-33 NETs concentration correlated significantly with patient disease activity assessed by the validated SLE Disease Activity Index (SLEDAI) [35] (Figure 2A and B), and longitudinal reduction in serum IL-33/MPO complexes was noted in patients with good clinical response to belimumab treatment [36] (Supplemental Figure S1A)

Summary

Introduction

Systemic Lupus Erythematosus (SLE) is the prototype systemic autoimmune disease characterized by dysregulated innate and adaptive immunity leading to generation of autoantibodies and formation of immune complexes (ICs) deposited to afflicted tissues such as the skin and kidneys [1]. One of the primary sources of IFN are plasmacytoid dendritic cells (pDCs) especially in response to Toll-like receptor(TLR)-7/9 signaling [8]. Genetic depletion [9] or inactivation [10] of pDCs diminishes IFN and ameliorates lupus-like disease in animal models and likewise, therapeutic targeting of pDCs and/or type I IFN has yielded promising results in human SLE [11, 12]. Various molecules can instruct IFN production by pDCs such as neutrophil-derived chromatin extracellular traps (NETs) complexed with autoantibodies and immunostimulatory proteins [13,14,15,16], the mechanisms that perpetuate IFN in SLE are incompletely understood

Methods

Results

Conclusion