A targetable 'rogue' neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS

Herrera, V.L.M.V.L.M.HerreraWalkey, A.J.A.J.WalkeyNguyen, M.Q.M.Q.NguyenGromisch, C.M.C.M.GromischMosaddhegi, J.Z.J.Z.MosaddhegiGromisch, M.S.M.S.GromischJundi, B.B.JundiLukassen, S.S.LukassenCarstensen, SaskiaSaskiaCarstensenDenis, R.R.DenisBelkina, A.C.A.C.BelkinaBaron, R.M.R.M.BaronPinilla-Vera, M.M.Pinilla-VeraMüller, MeikeMeikeMüllerKimberly, W.T.W.T.KimberlyGoldstein, J.N.J.N.GoldsteinLehmann, I.I.LehmannShih, A.R.A.R.ShihEils, R.R.EilsLevy, B.D.B.D.LevyRuiz-Opazo, N.N.Ruiz-Opazo2022-12-192022-12-192022https://publica.fraunhofer.de/handle/publica/43018010.1038/s41598-022-09343-12-s2.0-8512746593635379853Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable ‘rogue’ neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS.enA targetable 'rogue' neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDSjournal article