TLR-2 derangements likely play a significant role in the inflammatory response and thrombosis in patients with Ph(-) classical myeloproliferative neoplasm

Abstract

Abstract This study investigated TLRs on inflammatory pathways in Ph(-)MPNs. The results showed that TLR2 were increased in PV and MPN (PV + ET + MF), while TLR4 were only increased in MPN. TLR3, 7, and 9 were not elevated. We further cultured mdDC cells and demonstrating TLR2 elevated (TLR-E) patients secreted more cytokines than TLR2 normal (TLR-N), confirming the importance of TLR2. S100A9 and ROS were also measured, revealing S100A9 levels were increased in PV, MF, and MPN, while ROS levels increased only in MF and not in PV or ET. This data suggests that the pathogenesis of MPNs initially involves TLR2, minorly fromTLR4, along with S100A9 then induce ROS formation, JAK2 mutation,, leading ET and PV evolved into MF or leukemia. Further analysis of the data and studies, we found. 1) patients with Jak2 mutations or leukocytosis exhibited higher TLR2 expression, 2) cells from MPN patients displayed a stronger response to PM3CSK4 (TLR2 agonist) in leukocyte-platelet interaction compared to LPS ( TLR4 agonist). Adding TLR-2 inhibitor (not TLR-4 inhibitor) significantly attenuated this response, 3) TLR2-E patients experienced more thrombosis (29%) than TLR2-N (19%). These findings also suggest TLR2 plays a significant role in thrombosis in MPN.