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Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4<jats:sup>Cre<\/jats:sup>;Wt1<jats:sup>fl\/fl<\/jats:sup> CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages<jats:bold><jats:italic>.<\/jats:italic><\/jats:bold><\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that administering a single dose of atypical TLR2\/4 ligands (CS1 or CS2), 3\u00a0days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4<jats:sup>Cre<\/jats:sup>;Wt1<jats:sup>fl\/fl<\/jats:sup> CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206<jats:sup>+<\/jats:sup> and Arg1<jats:sup>+<\/jats:sup>) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RAR\u03b1, and RAR\u03b2, in the affected lungs and the diaphragm and in macrophages in vitro.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03384-7","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:02:40Z","timestamp":1729245760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toll-like receptors ligand immunomodulators for the treatment congenital diaphragmatic hernia"],"prefix":"10.1186","volume":"19","author":[{"given":"Mayte","family":"Vallejo-Cremades","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Merino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Carmona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"C\u00f3rdoba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Salvador","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leopoldo","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Antonio","family":"Tovar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel \u00c1ngel","family":"Llamas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram\u00f3n","family":"Mu\u00f1oz-Ch\u00e1puli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9223-5477","authenticated-orcid":false,"given":"Manuel","family":"Fresno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"issue":"9","key":"3384_CR1","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1111\/jpc.12508","volume":"50","author":"L Leeuwen","year":"2014","unstructured":"Leeuwen L, Fitzgerald DA. 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They followed ARRIVE guidelines and received approval from the Fundaci\u00f3n para la Investigaci\u00f3n Biom\u00e9dica del Hospital Universitario La Paz ethics committee (PROEX185\/15), by the Committee on the Ethics of Animal Experiments of the University of Malaga (permit code 2015\u20130028) and Comite\u0301 de \u00c9tica de la Direcci\u00f3n General del Medio Ambiente de la Comunidad de Madrid, (permits\u00a0PROEX 128\/15).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"386"}}