Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 175, Issue 23, Pages 4353-4370Publisher
WILEY
DOI: 10.1111/bph.14494
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Funding
- Junta de Andalucia [CTS 164]
- Spanish Ministry of Economy and Competitiveness [SAF2011-29648, AGL2015-67995-C3-3-R]
- European Union
- Instituto de Salud Carlos III
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Background and Purpose Experimental Approach Immunomodulatory tetracyclines are well-characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation. 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-derived macrophages and in dextran sodium sulfate (DSS)-induced 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-inflammatory effect of minocycline in DSS-colitis were then characterized. Key Results Conclusions and Implications 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-inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release in vitro, and while improving mucosal recovery in colitic mice, they up-regulated Ccl2, miR-142, miR-375 and Tlr4. In particular, minocycline initially enhanced IL-1 beta, IL-6, IL-22, GM-CSF and IL-4 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C(-)MHCII(+) macrophages, Tregs and type 2 intestinal immune responses. Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.
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