Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution
Article
Garrido-Mesa, J., Rodríguez-Nogales, A., Algieri, F., Vezza, T., Hidalgo-Garcia, L., Garrido-Barros, M., Utrilla, M.P., Garcia, F., Chueca, N., Rodriguez-Cabezas, M.E., Garrido Mesa, N. and Gálvez, J. 2018. Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution. British Journal of Pharmacology. 175 (23), pp. 4353-4370. https://doi.org/10.1111/bph.14494
Authors | Garrido-Mesa, J., Rodríguez-Nogales, A., Algieri, F., Vezza, T., Hidalgo-Garcia, L., Garrido-Barros, M., Utrilla, M.P., Garcia, F., Chueca, N., Rodriguez-Cabezas, M.E., Garrido Mesa, N. and Gálvez, J. |
---|---|
Abstract | 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. |
Journal | British Journal of Pharmacology |
Journal citation | 175 (23), pp. 4353-4370 |
ISSN | 0007-1188 |
Year | 2018 |
Publisher | Wiley |
Accepted author manuscript | License |
Digital Object Identifier (DOI) | https://doi.org/10.1111/bph.14494 |
Web address (URL) | https://doi.org/10.1111/bph.14494 |
Publication dates | |
Online | 05 Sep 2018 |
Publication process dates | |
Deposited | 04 Sep 2018 |
Accepted | 15 Aug 2018 |
Accepted | 15 Aug 2018 |
Funder | Instituto de Salud Carlos III |
Spanish Ministry of Economy and Competitiveness | |
Junta de Andalucía | |
Instituto de Salud Carlos III | |
Spanish Ministry of Economy and Competitiveness | |
Spanish Ministry of Economy and Competitiveness | |
Junta de Andalucía | |
Copyright information | This is the peer reviewed version of the following article: Garrido-Mesa, J. et. al., 2018, Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution, 175 (23) pp. 4353-4370, which has been published in final form at https://doi.org/10.1111/bph.14494. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
https://repository.uel.ac.uk/item/846w1
Download files
Accepted author manuscript
Garrido-Mesa J et al BJP 2018.pdf | ||
License: Wiley Terms and Conditions for Use of Self-Archived Versions |
170
total views245
total downloads0
views this month1
downloads this month