{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:22:01Z","timestamp":1792444921203,"version":"4.5.0"},"reference-count":157,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Lipopolysaccharide (LPS), also known as an endotoxin, is derived from Gram-negative bacteria. The intravenous administration of LPS induces an inflammatory response and causes systemic inflammation, such as cytokine storm. Gram-negative bacteria that produce LPS are found in the environment and digestive tract. The mucous membrane, the primary barrier between the interior of the body and the external environment, is constantly exposed to LPS. Moreover, no toxicity is observed when administering LPS through the mucous membranes of the mouth or skin. The presence of LPS in the mucous membranes is necessary not only for maintaining health but also for inducing preventive and therapeutic effects against multiple diseases when administered orally or topically. LPS is an environmental substance that is useful when administered to mucous membranes. The general information emphasizes the role of LPS as an inflammatory substance that occurs when administered intravenously. Therefore, the valuable role of LPS is unknown. Thus, mucosal administration of LPS has received little attention, and the mechanism underlying the expression of its beneficial effects has not been fully elucidated. We proposed a comprehensive concept, the \u201cmacrophage network,\u201d which proposes a regulatory system in which the mucosa receives environmental information, membrane-bound cytokines are expressed in phagocytes (macrophages), and these macrophages migrate distally to exert effects, such as anti-inflammatory and tissue repair effects, on distal tissues through cell-to-cell communication (juxtacrine signaling) with tissue macrophages. This macrophage network is effective not only for preventing and treating diseases but also for increasing the efficacy of pharmaceuticals. This review aims to investigate the preventive and therapeutic effects of oral and transdermal administration of LPS on various diseases and present an introduction to the concept of the macrophage network and the latest findings.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1563484","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:32:53Z","timestamp":1743399173000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Oral and transdermal administration of lipopolysaccharide safely enhances self-healing ability through the macrophage network"],"prefix":"10.3389","volume":"16","author":[{"given":"Gen-Ichiro","family":"Soma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Oda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vindy Tjendana","family":"Tjhin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chie","family":"Kohchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Inagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0952-7915(99)00046-1","article-title":"Tlr4: central component of the sole mammalian lps sensor","volume":"12","author":"Beutler","year":"2000","journal-title":"Curr Opin Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5396.2085","article-title":"Defective lps signaling in C3h\/hej and C57bl\/10sccr mice: mutations in tlr4 gene","volume":"282","author":"Poltorak","year":"1998","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.2.588","article-title":"A family of human receptors structurally related to drosophila toll","volume":"95","author":"Rock","year":"1998","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.424390","article-title":"Molecular mechanism responsible for the priming of macrophage activation","volume":"288","author":"Deng","year":"2013","journal-title":"J Biol Chem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594150","article-title":"Role of metabolic endotoxemia in systemic inflammation and potential interventions","volume":"11","author":"Mohammad","year":"2020","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.2174\/157488508783331243","article-title":"Preventative and therapeutic potential of lipopolysaccharide derived from edible gram-negative bacteria to various diseases","volume":"3","author":"Gen-Ichiro","year":"2008","journal-title":"Curr Drug Ther"},{"key":"B7","first-page":"3311","article-title":"Utilization of macrophages in anticancer therapy: the macrophage network theory","volume":"24","author":"Kohchi","year":"2004","journal-title":"Anticancer Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1263\/jbb.102.485","article-title":"Applications of lipopolysaccharide derived from pantoea agglomerans (Ip-pa1) for health care based on macrophage network theory","volume":"102","author":"Kohchi","year":"2006","journal-title":"J Biosci Bioeng"},{"key":"B9","doi-asserted-by":"publisher","first-page":"14387","DOI":"10.3390\/ijms241814387","article-title":"Utility of in vitro cellular models of low-dose lipopolysaccharide in elucidating the mechanisms of anti-inflammatory and wound-healing-promoting effects of lipopolysaccharide administration in vivo","volume":"24","author":"Honda","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.5604\/12321966.1203879","article-title":"Pantoea agglomerans: A mysterious bacterium of evil and good. 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