{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:07:42Z","timestamp":1788520062374,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020956","name":"Merck Healthcare KGaA","doi-asserted-by":"publisher","award":["10.13039\/100009945"],"award-info":[{"award-number":["10.13039\/100009945"]}],"id":[{"id":"10.13039\/100020956","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bioscript Group Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Excessive activation of toll-like receptor 7 and 8 (TLR7\/8) plays a role in the pathogenesis of autoimmune diseases and is associated with negative outcomes from viral infections. Neutrophil activation is highly inflammatory and mediates tissue damage. We explored the effects of TLR7\/8 activation in neutrophils to better understand neutrophil biology and evaluate the therapeutic utility of TLR7\/8 inhibitors in indications where neutrophils contribute to disease pathogenesis. We found that TLR8, but not TLR7, is active in human neutrophils. TLR8 activation led to increased interleukin-8 (IL-8) secretion and resulted in significant changes in gene expression, as determined by RNA sequencing, with increased expression of genes encoding cytokines and other inflammatory mediators. Type I interferon (IFN) also induced gene expression changes distinct from those induced by TLR8. Additionally, neutrophil extracellular traps (NET) formation and DNA release, or NETosis, was induced by TLR8 activation in IFN-primed neutrophils. Treatment with a TLR7\/8 inhibitor (CMPD2) effectively blocked IL-8 secretion and NETosis. In a Phase II clinical trial in COVID-19 pneumonia, TLR7\/8 inhibition with enpatoran affected neutrophil counts. Expression of NFKBIZ was induced by TLR8 in neutrophils in vitro and found to also be reduced by enpatoran in patients with COVID-19, suggesting it may be useful as a marker for TLR8-activated neutrophils and for identifying candidate diseases and patients that may benefit from treatment with a TLR7\/8 inhibitor. Overall, our findings provide new insights into TLR8 and neutrophil biology that have therapeutic implications in autoimmune diseases and immune-mediated inflammation.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf036","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T17:41:20Z","timestamp":1747849280000},"source":"Crossref","is-referenced-by-count":6,"title":["Toll-like receptor 8 activation induces a neutrophil inflammatory phenotype: therapeutic implications for the utility of toll-like receptor 8 inhibition"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-3012","authenticated-orcid":false,"given":"Angelika","family":"Schmidt","sequence":"first","affiliation":[{"name":"Merck Healthcare KGaA , Frankfurter Str. 250, 64293 Darmstadt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Coughlin","sequence":"additional","affiliation":[{"name":"EMD Serono Research 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