Inflammation induces pro-NETotic neutrophils via TNFR2 signaling

Friederike Neuenfeldt; Jan Christoph Schumacher; Ricardo Grieshaber-Bouyer; Jüri Habicht; Jutta Schröder-Braunstein; Annika Gauss; Uta Merle; Beate Niesler; Niko Heineken; Alexander Dalpke; Matthias M Gaida; Thomas Giese; Stefan Meuer; Yvonne Samstag; Guido Wabnitz

doi:10.1016/j.celrep.2022.110710

Inflammation induces pro-NETotic neutrophils via TNFR2 signaling

Cell Rep. 2022 Apr 19;39(3):110710. doi: 10.1016/j.celrep.2022.110710.

Authors

Affiliations

¹ Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
² Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
³ Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
⁴ Department of Human Molecular Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
⁵ Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, TU Dresden, 01069 Dresden, Germany.
⁶ Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany.
⁷ Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany. Electronic address: guido.wabnitz@immu.uni-heidelberg.de.

PMID: 35443164
DOI: 10.1016/j.celrep.2022.110710

Abstract

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.

Keywords: CP: Immunology; NETosis; neutrophil diversification; neutrophil subgroups; neutrophils; retrograde TNF signaling; ulcerative colitis.

MeSH terms

Extracellular Traps*
Humans
Inflammation
Neutrophils*
Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor Inhibitors

Substances

Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor Inhibitors