Study on the impact of Toll-like Receptor 4 (TLR4) modulation in rare inflammatory-fibrotic diseases

Fibrosis is an outcome of the repair response to tissue damage caused by inflammation. When the fibrotic process is excessive or dysregulated it leads to a pathological condition that can affect different organs and functions. Here, it is now clear that inflammation, which however is not the only trigger, plays a key role in the critical cellular process of fibroblast activation that leads to fibrosis up-set 1 . The recent discovery of complex crosstalk between fibrosis progression and inflammatory pathways underlines the central role of Toll-like Receptor 4 (TLR4) and its potential as a new drug target 2 . Here it is proposed an in vitro screening on cellular models of fibrosis with TLR4 antagonists to identify new potential drugs targeting Idiopathic Pulmonary Fibrosis (IPF), a rare fibrotic pathology where a pivotal role of TLR4- mediated inflammation has been observed 3 4 . In particular, in this work, we started to test the possible impact on fibrosis phenotype up-set of FP7 and FP12 that showed inhibition activity against TRL4 activation by LPS in a dose-dependent way in both human and murine cells 5 References: 1. Upcoming treatments for morphea - Wenzel - 2021 - Immunity, Inflammation and Disease - Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.475. 2. Bhattacharyya, S. et al. Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis. Frontiers in Immunology 9, (2018). 3. Emerging Roles of Innate Immune Signaling and Toll-Like Receptors in Fibrosis and Systemic Sclerosis | SpringerLink. https://link.springer.com/article/10.1007/s11926-014-0474-z. 4. Bolourani, S., Brenner, M. & Wang, P. The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J Mol Med 99, 1373–1384 (2021). 5. Facchini, F. A. et al. Structure–Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists. J. Med. Chem. 61, 2895–2909 (2018).