Fabio Alessandro Facchini1, Davide Di Fusco2, Simona Barresi1, Andrea Luraghi1, Alberto Minotti1, Francesca Granucci1, Giovanni Monteleone2, Francesco Peri3, Ivan Monteleone4. 1. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy. 2. Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy. 3. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy. francesco.peri@unimib.it. 4. Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy. ivan.monteleone@uniroma2.it.
Abstract
PURPOSE: The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7. METHODS: The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBD patients, and in a mouse model of ulcerative colitis. RESULTS: FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88- and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of pro-inflammatory cytokines. CONCLUSIONS: This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.
PURPOSE: The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7. METHODS: The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBDpatients, and in a mouse model of ulcerative colitis. RESULTS: FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88- and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of pro-inflammatory cytokines. CONCLUSIONS: This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.
Authors: Charys Palmer; Fabio A Facchini; Richard Po Jones; Frank Neumann; Francesco Peri; Grisha Pirianov Journal: Innate Immun Date: 2021-04 Impact factor: 2.680