In:
The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 1_Supplement ( 2021-05-01), p. 109.01-109.01
Abstract:
A computational platform, the Boolean network explorer (BoNE) has recently been developed; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE derived Inflammatory Bowel Disease (IBD)-map and prioritize two nuclear receptors, PPARa and PPARg. Balanced agonism of PPARa/g was predicted to impact macrophage function, ameliorate colitis in network-prioritized animal models, ‘reset’ the gene expression network from disease to health. Predictions were validated using a balanced and potent PPARa/g-dual agonist (PAR5359) in two murine models, i.e., Citrobacter rodentium- and DSS-induced colitis. Mechanistically, we show that balanced dual agonists promote bacterial clearance more efficiently than individual agonists both in vivo and in vitro, through the controlled induction of pro-inflammatory cytokines, cellular ROS and gut-barrier protection. PPARa is required and its agonism is sufficient to induce the pro-inflammatory response that is essential for bacterial clearance and immunity, but PPARg-agonism blunts these responses, delays microbial clearance. Balanced agonists achieved controlled inflammation, barrier protection and reversed the network towards the healthy side of disease. When tested on IBD-patients-derived PBMCs, PAR5359 reversed the defective bacterial clearance observed in these subjects. These findings not only deliver a macrophage modulator in IBD but also highlight the potential of BoNE to accelerate and enhance the precision of drug discovery in various diseases.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.206.Supp.109.01
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2021
detail.hit.zdb_id:
1475085-5
detail.hit.zdb_id:
3056-9
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