Modelling the effects of PPARβδ of innate inflammatory responses in lung tissues

Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells whose signaling controls inflammation and metabolism. However, there are great discrepancies in understanding the role of PPARβ/δ, having both anti- and pro-effects on inflammation. Understanding the PPARβ/δ mechanism of action may provide new molecular mechanisms for treating a variety of inflammatory-related diseases. We studied the PPARβ/δ-regulation of LPS-induced inflammation of pulmonary artery, bronchi and parenchyma from rat, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS-induced inflammation is largely regulated by PPARβ/δ in the pulmonary artery, but it is a minor factor in bronchi or parenchyma. Agonists do not significantly inhibit inflammation, but activates the PPARβ/δ induction mode of action. Surprisingly, co-incubation of the tissue with agonist plus antagonist shows anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, indicating that the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. Us of Computational chemistry methods indicates that PPARβ/δ agonists are predicted to form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favorable binding energies and the feasibility of simultaneous binding of two ligands in the PPARβ/δ binding pocket. In summary, this study provides novel insight into the complex relationship between ligand binding profiles and functional outcomes in a rat lung inflammation model, which will help inform the design of novel therapies for inflammatory lung diseases.