Inflammation induces pro-NETotic neutrophils via TNFR2 signaling

Highlights

• Priming induces neutrophil diversification into CCR5⁻ and CCR5⁺ cells

• TNFR2 signaling renders CCR5⁺ neutrophils pro-NETotic by ELANE upregulation

• CCR5⁺ neutrophils appear in the lamina propria of ulcerative colitis patients

• Retrograde TNF signaling induces NETosis of CCR5⁺ neutrophils

Summary

Cytokines released during chronic inflammatory diseases induce pro-inflammatory properties in polymorphonuclear neutrophils (PMNs). Here, we describe the development of a subgroup of human PMNs expressing CCR5, termed CCR5⁺ PMNs. Auto- and paracrine tumor necrosis factor (TNF) signaling increases intracellular neutrophil elastase (ELANE) abundance and induces neutrophil extracellular traps formation (NETosis) in CCR5⁺ PMNs, and triggering of CCR5 amplifies NETosis. Membranous TNF (mTNF) outside-in signaling induces the formation of reactive oxygen species, known activators of NETosis. In vivo, we find an increased number of CCR5⁺ PMNs in the peripheral blood and inflamed lamina propria of patients with ulcerative colitis (UC). Notably, failure of anti-TNF therapy is associated with higher frequencies of CCR5⁺ PMNs. In conclusion, we identify a phenotype of pro-NETotic, CCR5⁺ PMNs present in inflamed tissue in vivo and inducible in vitro. These cells may reflect an important component of tissue damage during chronic inflammation and could be of diagnostic value.