Garrido-Mesa, JRodríguez-Nogales, AAlgieri, FVezza, THidalgo-Garcia, LGarrido-Barros, MUtrilla, M PGarcia, FChueca, NRodriguez-Cabezas, M EGarrido-Mesa, NGálvez, J2023-01-252023-01-252018-10-15http://hdl.handle.net/10668/12909Immunomodulatory 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. 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-1β, 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.enAnimalsAnti-Inflammatory Agents, Non-SteroidalColitisDextran SulfateImmunologic FactorsInflammationIntestinesMiceMucous MembraneRAW 264.7 CellsTetracyclinesresearch article30184260open access10.1111/bph.144941476-5381PMC6240124https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.14494https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240124/pdf