Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci

Microbial Cell Factories

Research

Luis G Bermúdez-Humarán¹  Camille Aubry¹  Philippe Langella¹  Pascale Kharrat¹  Jean-Michel Sallenave²  Laurence Rous-Martin³  Céline Deraison³  Jean-Paul Motta⁴  Nathalie Vergnolle⁵ 

[1] INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France;AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France;INSERM U874, Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France;INSERM U1152, Faculté de Médecine site Bichat, Université Paris Diderot, 16, rue Henri Huchard, 75018, Paris, France;Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France;Inserm, U1043, F-31300, Toulouse, France;CNRS, U5282, F-31300, Toulouse, France;Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31300, Toulouse, France;Inserm, U1043, F-31300, Toulouse, France;CNRS, U5282, F-31300, Toulouse, France;Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31300, Toulouse, France;Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada;Inserm, U1043, F-31300, Toulouse, France;CNRS, U5282, F-31300, Toulouse, France;Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31300, Toulouse, France;Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France;

关键词: Elafin;    Proteases;    Inflammation;    Colitis;    Inflammatory bowel disease;    Lactococcus lactis;    Probiotics;   

DOI  :  10.1186/s12934-015-0198-4

 received in 2014-08-28, accepted in 2015-01-23,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundDifferent studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD).MethodsIn order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-β1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis.ResultsOur results show that oral administration of recombinant L. lactis strains expressing either IL-10 or TGF-β1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect.ConclusionsAltogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLAB at the mucosal level for IBD treatment.

【 授权许可】

Unknown   
© Bermúdez-Humarán; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.