Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

Abstract

24Chemerin, a chemoattractant protein, is involved in endothelial dysfunction and 25 vascular inflammation in pathological conditions. In a recent study, we observed the 26 upregulation of chemerin in endothelial cells following in vitro treatment with T. 27 pallidum. Here, we investigated the role of chemerin in endothelial cells dysfunction 28 induced by the T. pallidum predicted membrane protein Tp0965. Following 29 stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, 30 chemerin and its ChemR23 receptor were up-regulated, companied with elevated 31 expression of TLR2. Furthermore, chemerin from HUVECs activated endothelial cells 32 via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by 33 upregulated expression of ICAM-1, E-selectin and MMP-2. Activation of endothelial 34 cells depended on the MAPK signaling pathway. In addition, Tp0965-induced 35 chemerin promoted monocytes migration to endothelial cells, also via 36 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 37 in monocytes migration in response to chemerin/ChemR23. Our results highlight the 38 role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to 39 the immunopathogenesis of vascular inflammation of syphilis.40 Author summary 41 Treponema pallidum is the spirochete of syphilis, which causes a chronic system 42 inflammation. Endothelium damage caused by this bacterium is the key step in the 43 systemic dissemination and pathophysiology of syphilis, particularly cardiovascular 44 syphilis and neurosyphilis. In this study, we show a novel molecular mechanism of 3 45 endothelium damage induce by Treponema pallidum predicted membrane protein 46 Tp0965. Chemerin is a recently identified adipocytokine and chemoattractant protein 47 with a crucial role in endothelial dysfunction and vascular inflammation in pathological 48 conditions. Our data show that Tp0965 up-regulated the expression of chemerin and its 49 ChemR23 receptor by endothelial cells in vitro. Furthermore, chemerin from HUVECs 50 activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine 51 manner and depended on the MAPK signaling pathway. In addition, Tp0965-induced 52 chemerin promoted monocytes migration to endothelial cells, also via 53 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 54 in monocytes migration in response to chemerin/ChemR23. These findings contribute 55 to the immunopathogenesis of vascular inflammation of syphilis. 56 57 Introduction 58 Treponema pallidum subsp. pallidum (T. pallidum) is the spirochete of syphilis, a 59 sexually transmitted infection that remains an important public health problem around 60 the world [1]. Infection by this bacterium causes a chronic system inflammation, and if 61 untreated can seriously and irreversibly damage the nervous and cardiovascular system.62 Cardiovascular syphilis is associated with multiple clinical syndromes, of which aortic 63 aneurysms, aortic insufficiency,...