{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:13:29Z","timestamp":1780082009653,"version":"3.54.0"},"reference-count":59,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T00:00:00Z","timestamp":1693008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage\u2019s sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1(+) and Spike-1(\u2212) lungs (p &lt; 0.0001), and a macrophage shift with important down-regulation of GAL-3(+) alveolar macrophages associated with Spike-1 persistence (p &lt; 0.05), in favor of CD163(+) myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19.<\/jats:p>","DOI":"10.3390\/ijms241713259","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T01:56:57Z","timestamp":1693187817000},"page":"13259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Role of Toll-like Receptor-4 in Macrophage Imbalance in Lethal COVID-19 Lung Disease, and Its Correlation with Galectin-3"],"prefix":"10.3390","volume":"24","author":[{"given":"Maria Carmela","family":"Pedicillo","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4955-2039","authenticated-orcid":false,"given":"Ilenia Sara","family":"De Stefano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Zamparese","sequence":"additional","affiliation":[{"name":"Legal Medicine Unit, Ascoli Piceno Hospital C-G. Mazzoni, Viale Degli Iris 13, 63100 Ascoli Piceno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Barile","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Meccariello","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Agostinone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2362-5022","authenticated-orcid":false,"given":"Giuliana","family":"Villani","sequence":"additional","affiliation":[{"name":"Policlinico Riuniti, University-Hospital, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Colangelo","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"},{"name":"Cancer Cell Signalling Unit, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), IRCCS Fondazione Casa Sollievo della Sofferenza, Viale Cappuccini sc.c., San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-7841","authenticated-orcid":false,"given":"Gaetano","family":"Serviddio","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6330-806X","authenticated-orcid":false,"given":"Tommaso","family":"Cassano","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, Viale L.Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cL Vanvitelli\u201d, via Luciano Armanni, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8340-3184","authenticated-orcid":false,"given":"Renato","family":"Franco","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cL Vanvitelli\u201d, via Luciano Armanni, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Pannone","sequence":"additional","affiliation":[{"name":"Federico II, Department of Clinical Medicine and Surgery, School of medicine and Surgery, University of Naples, via Sergio Pasini, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Zito Marino","sequence":"additional","affiliation":[{"name":"Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cL Vanvitelli\u201d, via Luciano Armanni, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Campania \u201cL Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Municin\u00f2","sequence":"additional","affiliation":[{"name":"Forensic Medicine Unit, \u201cS. 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