Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution

Background and Purpose: Immunomodulatory tetracyclines are well-characterised drugs with a pharmacological potential beyond their antibiotic properties. Particulaarly, minocycline and doxycycicline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophages. Therefore, we aimed to characterise the mechanism behind their effect in acute intestinal inflammation. Experimental Approach: A comparative pharmacological study was first used to elucidate teh most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline, tigecycline and other antibiotic or immunomodulatory drugs were assessed in bone-marrow derived macrophages and in DSS-induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. Then, the sequential immune events that mediate the intestinal anti-inflammatory effect of minocycline in DSS-colitis were characterised. Key Results: We have identified a novel immunomodulatory activity of tetracyclines, potentiating the innate immune response and leading to an 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 potentiate macrophage cytokine release in vitro and, while improving mucosal recovery in colitic mice, they up-regulate Ccl2, miR-142, miR-375 and Tlr4. In particular, minocycline initially enhances 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. Conclusion and Implications: Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.