Tp47 promoted the phagocytosis of HMC3 cells though autophagy induced by endoplamic reticlum stress

Abstract

Background Central nervous system damage is an essential clinical feature that occurs in the early or late stages of syphilis infection. The abnormal enhancement of microglial phagocytosis can cause damage to the nervous system. However, the contribution of abnormally enhanced microglial phagocytosis to the pathogenesis of Treponema pallidum subsp. pallidum (T. pallidum) infection remains unknown. Objectives In this study, we sought to determine the role of recombinant T. pallidum Tp47 in promoting microglia phagocytosis and its associated mechanisms. Methods Microglial HMC3 cells were used to investigate the effect of the Tp47 on phagocytosis and the roles of autophagy and endoplasmic reticulum stress in Tp47‐induced phagocytosis. Results HMC3 cells exhibited obvious phagocytosis when stimulated with Tp47. The levels of P62 degradation, Beclin1 expression and the LC3II/LC3I ratio were significantly elevated, and the fusion of autophagosomes and lysosomes was promoted in Tp47‐stimulated HMC3 cells. Treatment with the autophagy inhibitors 3‐MA and Baf A1 inhibited Tp47‐induced phagocytosis. Meanwhile, the endoplasmic reticulum stress markers PERK, IRE1α, GRP78, ATF4 and XBP1s were upregulated in Tp47‐stimulated HMC3 cells. In addition, we found that TUDCA could inhibit Tp47‐induced expression of IRE1α but not PERK or ATF4. 4‐PBA inhibited TP47‐induced PERK and ATF4 protein expression but did not inhibit IRE1α expression. Attenuation of endoplasmic reticulum stress by administration of TUDCA and 4‐PBA abrogated Tp47‐mediated autophagy. Conclusions These results suggested that Tp47 activated autophagy through two key pathways associated with endoplasmic reticulum stress, PERK/ATF4 and IRE1/XBP1, to promote phagocytosis in HMC3 cells. These findings provided a basis for the understanding of the pathophysiology of neurological disorders that occur during the course of syphilis.

Treponema pallidum membrane protein Tp47 induced autophagy and inhibited cell migration in HMC3 cells via the PI3K/AKT/FOXO1 pathway

“…Western blotting was performed as described previously. 4 Antibodies against the following proteins were used: PI3K…”

“…Our previous research revealed that the T. pallidum membrane protein Tp47 promoted microglial autophagy 4 . Autophagy is a highly preserved process of self‐digestion involving the breakdown of organelles, protein clusters and cytoplasmic proteins by lysosomes 5 .…”

Recombinant Treponema pallidum protein Tp47 promoted the phagocytosis of macrophages by activating NLRP3 inflammasome induced by PKM2‐dependent glycolysis

“…Previous studies have shown that T. pallidum promotes macrophages phagocytosis through the NLRP3 inflammasome to further clean T. pallidum, 3 and Tp47, a T. pallidum antigen, showed remarkable immunogenicity 20 and enhanced the capacity of phagocytosis in microglia cells. 18 Recent studies have suggested that glycolysis is involved in immune responses. 21 Our study found that Tp47 promotes macrophage phagocytosis by activating the NLRP3 inflammasome induced by PKM2dependent glycolysis.…”

“…Our previous study showed that Tp47 increases the phagocytic capacity of microglial cells. 18 In the current study, we investigated the role of glycolysis in activating the NLRP3 inflammasome to regulate phagocytosis in macrophages in response to Tp47 stimulation and explored the potential molecular mechanism that regulates the high-glycolytic phenotype.…”

Editorial: Neurosyphilis: epidemiology, clinical manifestations, diagnosis, immunology and treatment

“…Tp -specific protein biomarkers can also be explored by mass spectrometry (21,22). The roles of these proteins were explored, delving into the promotion of proinflammatory cytokine secretion (23) and cell migration (Tp0136), apoptosis (Tp0751), autophagy and adhesion (Tp768) (24)(25)(26), inducing angiogenesis (Tp47), and stimulating human platelet activation and aggregation (Tp0136) (27). This research facilitates the development of biomarker or vaccine candidates (Tp0954), especially in understanding neuropathogenesis.…”