Evaluation of Phosphatidylcholine A Tlr 4 Antagonist In Systemic Vasculitis Model

Abstract

Toll-like Receptor-4 (TLR-4) is a transmembrane protein of the pattern recognition receptor (PRR) family. TLR-4 is a key component of the innate immune system that triggers the release of various proinflammatory cytokines through initiation of Nuclear factor-and#954;B (NF-and#954;B) via Myeloid Differentiation Primary Response Gene 88 (MyD88)-dependent intracellular signaling pathway. On the contrary, inhibition of TLR-4 has reduced inflammatory responses. Not only does TLR-4 stimulation affect innate and adaptive immunity, but it also plays an important role in the initiation and progression of vasculitis. Hence, blocking TLR-4 may be beneficial in treating vasculitis. Current vasculitis treatment involves immunosuppressant agents, which can cause serious side effects when used for a long period. Therefore, a prominent non-steroidal therapeutic agent is needed for the treatment of vasculitis. Our study investigated the feasibility of developing and validating a new animal model by using the combination of Ovalbumin (OVA) and Lipopolysaccharide (LPS). The results showed that OVA and LPS induced vasculitis phenotypes in small, medium, and large vessels in rats. Additionally, phosphatidylcholine (PC), a TLR-4 antagonist was evaluated for its therapeutic potential in OVA-LPS induced systemic vasculitis. Phosphatidylcholine treatment had shown protection against OVA-LPS induced systemic vasculitis in rats. In addition, a computational in-silico study was conducted to determine the binding affinity of phosphatidylcholine on proinflammatory cytokines in the body (IL-1and#946;, IL-6 and TNF-and#945;). The results demonstrated a notable interaction of PC with the selected Cytokines. In conclusion, PC could be a viable alternative to steroid replacement therapy and a possible emerging therapy in vasculitis, acting by antagonizing TLR-4 and inhibiting the underlying transcription of pro-inflammatory cytokines. newline