{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:35:57Z","timestamp":1792787757349,"version":"4.5.0"},"reference-count":33,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"EU-Next generation","award":["CUP H53D23004750006"],"award-info":[{"award-number":["CUP H53D23004750006"]}]},{"name":"university of maryland institute for clinical and translational research","award":["#1UL1TR003098"],"award-info":[{"award-number":["#1UL1TR003098"]}]},{"DOI":"10.13039\/501100024598","name":"British Heart Foundation Centre of Regenerative Medicine","doi-asserted-by":"publisher","award":["PG\/20\/10072"],"award-info":[{"award-number":["PG\/20\/10072"]}],"id":[{"id":"10.13039\/501100024598","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Innate Immun"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Acute Lung Injuries (ALI) are a severe consequence of influenza-induced cytokine storm that can cause respiratory failure and death. It has been demonstrated that Toll-like Receptor 4 (TLR4) is involved in cytokine storm and that TLR4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice are protected against ALI. Therefore, TLR4 is a prime target for protection against ALI. FP12 is a known TLR4 antagonist that reduces TLR4-dependent immune activation and it is a promising lead compound for the treatment of innate immunity related pathologies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We present here the preclinical development of FP12 as an anti-inflammatory lead compound acting on influenza-induced ALI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vitro: We pre-treated THP-1 cells with FP12 (10\u2005\u03bcM) for 0.5\u2005h, then exposed to LPS (100\u2005ng\/ml) for 0 to 16\u2005h. In some experiments, cells were simultaneously incubated with FP12 and LPS, or FP12 was added 30\u2005min after LPS. Cytokine levels were measured by Western blot and ELISA assays. In vivo: WT C57BL\/6J mice were infected with mouse-adapted influenza virus (PR8). Two days after infection, mice received either vehicle, FP7 (200\u2005\u00b5g\/mouse), or FP12 (200\u2005\u00b5g\/mouse) once daily (Day 2 to Day 6). Mice were monitored daily for survival for 14 days. Data were collected through histological staining, qRT-PCR, and ELISA assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FP12 treatment inhibited both LPS- and HMGB1-induced TLR4 intracellular pathways (MyD88 and TRIF) leading to significantly reduced levels of a variety of proinflammatory cytokines including Type I interferon (IFN-\u03b2), highlighting its effectiveness in controlling proinflammatory protein production and reducing inflammation. FP12 protected mice therapeutically from influenza virus-induced lethality and reduced both cytokine gene expression and High Mobility Group Box 1 (HMGB1) levels in the lungs as well as ALI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>FP12 can antagonize TLR4 activation in vitro and protects mice from severe influenza infection, most likely by reducing the TLR4-dependent cytokine storm mediated by danger-associated molecular patterns (DAMPs).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17534259241313201","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T14:09:38Z","timestamp":1741097378000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Preclinical development of the TLR4 antagonist FP12 as a drug lead targeting the HMGB1\/MD-2\/TLR4 axis in lethal influenza infection"],"prefix":"10.1177","volume":"31","author":[{"given":"Kari Ann","family":"Shirey","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Romerio","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Monsoor","family":"Shaik","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Leake","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Health and Life Sciences Building, University of Reading, Reading, Berkshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charys","family":"Palmer","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Anglia Ruskin University, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Skupinska","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Anglia Ruskin University, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2242-251X","authenticated-orcid":false,"given":"Jules","family":"Paton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grisha","family":"Pirianov","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Anglia Ruskin University, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge CG","family":"Blanco","sequence":"additional","affiliation":[{"name":"Sigmovir Biosystems Inc., Rockville, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie N","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3417-8224","authenticated-orcid":false,"given":"Francesco","family":"Peri","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"bibr1-17534259241313201","doi-asserted-by":"publisher","DOI":"10.1038\/nature12118"},{"key":"bibr2-17534259241313201","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.141"},{"key":"bibr3-17534259241313201","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.002"},{"key":"bibr4-17534259241313201","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.705080"},{"key":"bibr5-17534259241313201","doi-asserted-by":"crossref","unstructured":"Andersson U, Yang H, Harris H. High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. 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