{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:18:31Z","timestamp":1790565511352,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergies and Infectious Diseases (NIAID)","award":["SC1AI155439"],"award-info":[{"award-number":["SC1AI155439"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There is a present need to develop alternative biotherapeutic drugs to mitigate the exacerbated inflammatory immune responses characteristic of sepsis. The potent endotoxin lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membrane, activates the immune system via Toll-like receptor 4 (TLR4), triggering macrophages and a persistent cascade of inflammatory mediators. Our previous studies have demonstrated that Fh15, a recombinant member of the Fasciola hepatica fatty acid binding protein family, can significantly increase the survival rate by suppressing many inflammatory mediators induced by LPS in a septic shock mouse model. Although Fh15 has been proposed as a TLR4 antagonist, the specific mechanisms underlying its immunomodulatory effect remained unclear. In the present study, we employed a quantitative proteomics approach using tandem mass tag (TMT) followed by LC-MS\/MS analysis to identify and quantify differentially expressed proteins that participate in signaling pathways downstream TLR4 of macrophages, which can be dysregulated by Fh15. Data are available via ProteomeXchange with identifier PXD065520. Based on significant fold change (FC) cut-off of 1.5 and p-value \u2264 0.05 criteria, we focused our attention to 114 proteins that were upregulated by LPS and downregulated by Fh15. From these proteins, TNF\u03b1, IL-1\u03b1, Lck, NOS2, SOD2 and CD36 were selected for validation by Western blot on murine bone marrow-derived macrophages due to their relevant roles in the NF-\u03baB, iNOS, oxidative stress, and phagosome signaling pathways, which are closely associated with sepsis pathogenesis. These results suggest that Fh15 exerts a broad spectrum of action by simultaneously targeting multiple downstream pathways activated by TLR4, thereby modulating various aspects of the inflammatory responses during sepsis.<\/jats:p>","DOI":"10.3390\/ijms26146914","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T13:33:27Z","timestamp":1752845607000},"page":"6914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quantitative Proteomics Reveals Fh15 as an Antagonist of TLR4 Downregulating the Activation of NF-\u03baB, Inducible Nitric Oxide, Phagosome Signaling Pathways, and Oxidative Stress of LPS-Stimulated Macrophages"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-2804","authenticated-orcid":false,"given":"Albersy","family":"Armina-Rodriguez","sequence":"first","affiliation":[{"name":"Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca N.","family":"Vald\u00e9s Fernandez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7046-1076","authenticated-orcid":false,"given":"Carlimar","family":"Ocasio-Malav\u00e9","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadira M.","family":"Cantres Rosario","sequence":"additional","affiliation":[{"name":"Translational Proteomics Center, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7224-2349","authenticated-orcid":false,"given":"Kelvin","family":"Carrasquillo Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Integrated Informatics Services, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-8206","authenticated-orcid":false,"given":"Loyda M.","family":"Mel\u00e9ndez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"},{"name":"Translational Proteomics Center, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-6744","authenticated-orcid":false,"given":"Abiel","family":"Roche Lima","sequence":"additional","affiliation":[{"name":"Integrated Informatics Services, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-8671","authenticated-orcid":false,"given":"Eduardo L.","family":"Tosado Rodriguez","sequence":"additional","affiliation":[{"name":"Integrated Informatics Services, Research Capacity Core, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"},{"name":"School of Dental Medicine, Universidad Ana G. Mendez, Gurabo, PR 00778, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-2550","authenticated-orcid":false,"given":"Ana M.","family":"Espino","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/2049-632X.12080","article-title":"Helminths and their implication in sepsis\u2014A new branch of their immunomodulatory behaviour?","volume":"69","author":"Hubner","year":"2013","journal-title":"Pathog. 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