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., 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.
AuthorsGarrido-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., 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.

JournalBritish Journal of Pharmacology
Journal citation175 (23), pp. 4353-4370
ISSN0007-1188
Year2018
PublisherWiley
Accepted author manuscript
License
Digital Object Identifier (DOI)doi:10.1111/bph.14494
Web address (URL)https://doi.org/10.1111/bph.14494
Publication dates
Online05 Sep 2018
Publication process dates
Deposited04 Sep 2018
Accepted15 Aug 2018
Accepted15 Aug 2018
FunderInstituto 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 informationThis 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.
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