{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:11:09Z","timestamp":1793373069163,"version":"4.5.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009123","name":"Norges Teknisk-Naturvitenskapelige Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009123","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Human metapneumovirus (HMPV) is a major cause of acute respiratory disease in children, the elderly, and immunocompromised individuals. While pro-inflammatory cytokines and type I interferons (IFNs) are important for antiviral defense, excessive tumor necrosis factor (TNF) is associated with severe disease in HMPV and other respiratory infections. Hence, defining regulatory mechanisms by which HMPV induces TNF and IFN-\u03b2 is important for therapeutic strategies in airway disease. The immunoregulatory receptors Toll-like receptor (TLR)4 and signaling lymphocytic activation molecule family 1 (SLAMF1) mediate TNF and IFN-\u03b2 expression in response to LPS and Gram-negative bacteria, but their involvement in HMPV-stimulated cytokine expression is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the kinetics of\n                      <jats:italic>TNF<\/jats:italic>\n                      and\n                      <jats:italic>IFNB1<\/jats:italic>\n                      expression in human monocyte-derived macrophages (MDMs) and THP-1 macrophage-like cells. The impact of SLAMF1 and TLR4 on\n                      <jats:italic>TNF<\/jats:italic>\n                      ,\n                      <jats:italic>IFNB1<\/jats:italic>\n                      , and p38 MAPK was determined after their overexpression or knockout in THP-1 cells or silencing in MDMs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TLR4 knockout reduced\n                      <jats:italic>TNF<\/jats:italic>\n                      but not\n                      <jats:italic>IFNB1<\/jats:italic>\n                      induced by HMPV, whereas SLAMF1 silencing reduced both cytokines. Overexpression of TLR4 or SLAMF1 enhanced p38 MAPK activation and TNF secretion, while silencing of TLR4 or SLAMF1 reduced p38 MAPK activation and TNF secretion. Pharmacological inhibition of p38 MAPK reduced both\n                      <jats:italic>TNF<\/jats:italic>\n                      and\n                      <jats:italic>IFNB1<\/jats:italic>\n                      , confirming its essential role in cytokine induction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, our findings identify TLR4 and SLAMF1 as key regulators of early HMPV-induced inflammation via p38 MAPK. SLAMF1 additionally influences IFN-\u03b2 responses and appears to affect viral replication dynamics. These insights suggest that targeting SLAMF1\u2013TLR4 signaling may offer a therapeutic strategy to limit TNF-driven pathology in HMPV infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1697494","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:18:30Z","timestamp":1763529510000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The immune receptors TLR4 and SLAMF1 regulate TNF release by human metapneumovirus in human macrophages"],"prefix":"10.3389","volume":"16","author":[{"given":"Katja","family":"S\u00e6terhaug 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