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.
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•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
Neuenfeldt et al. show that neutrophil priming induces dichotomous expression of CCR5. TNFR2 signaling increases ELANE expression in CCR5+ neutrophils. CCR5 triggering or reverse signaling of membrane-bound TNF activates ELANE, leading to enhanced NETosis. Pro-NETotic CCR5+ neutrophils in the lamina propria of ulcerative colitis patients may affect the success of anti-TNF therapies.
