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Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro\u2010inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>A comparative pharmacological study was initially used to elucidate the most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline and tigecycline; other antibiotic or immunomodulatory drugs were assessed in bone marrow\u2010derived macrophages and in dextran sodium sulfate (DSS)\u2010induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. The sequential immune events that mediate the intestinal anti\u2010inflammatory effect of minocycline in DSS\u2010colitis were then characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Novel immunomodulatory activity of tetracyclines was identifed; they potentiated the innate immune response and enhanced resolution of inflammation. This is also the first report describing the intestinal anti\u2010inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release <jats:italic>in vitro<\/jats:italic>, and while improving mucosal recovery in colitic mice, they up\u2010regulated <jats:italic>Ccl2<\/jats:italic>, <jats:italic>miR\u2010142<\/jats:italic>, <jats:italic>miR\u2010375<\/jats:italic> and <jats:italic>Tlr4<\/jats:italic>. In particular, minocycline initially enhanced IL\u20101\u03b2, IL\u20106, IL\u201022, GM\u2010CSF and IL\u20104 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C<jats:sup>\u2212<\/jats:sup>MHCII<jats:sup>+<\/jats:sup> macrophages, Tregs and type 2 intestinal immune responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14494","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T16:07:08Z","timestamp":1536163628000},"page":"4353-4370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution"],"prefix":"10.1111","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6420-9055","authenticated-orcid":false,"given":"J","family":"Garrido\u2010Mesa","sequence":"first","affiliation":[{"name":"CIBER\u2010EHD, Department of Pharmacology, ibs. 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