{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:53:04Z","timestamp":1791341584821,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012437","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072459"],"award-info":[{"award-number":["82072459"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272258"],"award-info":[{"award-number":["82272258"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The ability of\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    ) to survive within macrophages is a critical strategy for immune evasion, contributing to the pathogenesis and progression of osteomyelitis. However, the underlying mechanisms remain poorly characterized. This study discovered that inhibiting the MEK1\/2 pathway reduced bacterial load and mitigated bone destruction in a mouse model of\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    osteomyelitis. Histological staining revealed increased phosphorylated MEK1\/2 levels in bone marrow macrophages surrounding abscess in the mouse model of\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    osteomyelitis. Activation of MEK1\/2 pathway and its roles in impairing macrophage bactericidal function were confirmed in primary mouse bone marrow-derived macrophages (BMDMs). Transcriptome analysis and\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments demonstrated that\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    activates the MEK1\/2 pathway through EGFR signaling. Moreover, we found that excessive activation of EGFR-MEK1\/2 cascade downregulates mitochondrial reactive oxygen species (mtROS) levels by suppressing Chek2 expression, thereby impairing macrophage bactericidal function. Furthermore, pharmacological inhibition of EGFR signaling prevented upregulation of phosphorylated MEK1\/2 and restored Chek2 expression in macrophages, significantly enhancing\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    clearance and improving bone microstructure\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These findings highlight the critical role of the EGFR-MEK1\/2 cascade in host immune defense against\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    , suggesting that\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    may reduce mtROS levels by overactivating the EGFR-MEK1\/2 cascade, thereby suppressing macrophage bactericidal function. Therefore, combining EGFR-MEK1\/2 pathway blockade with antibiotics could represent an effective therapeutic approach for the treatment of\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    osteomyelitis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012437","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T13:47:32Z","timestamp":1722865652000},"page":"e1012437","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["EGFR-MEK1\/2 cascade negatively regulates bactericidal function of bone marrow macrophages in mice with Staphylococcus aureus osteomyelitis"],"prefix":"10.1371","volume":"20","author":[{"given":"Mingchao","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingsheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chubin","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mankai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0992-5013","authenticated-orcid":true,"given":"Xianrong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"issue":"6","key":"ppat.1012437.ref001","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.chom.2013.05.015","article-title":"Staphylococcus 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