1. Academic Validation
  2. Treponema pallidum Flagellin FlaB3 Activates Inflammation and Inhibits Autophagy in HMC3 Cells via the TLR4 Pathway

Treponema pallidum Flagellin FlaB3 Activates Inflammation and Inhibits Autophagy in HMC3 Cells via the TLR4 Pathway

  • ACS Infect Dis. 2025 Mar 14;11(3):773-783. doi: 10.1021/acsinfecdis.4c01064.
Fangzhi Du 1 Zhiyu Lu 1 Qingyun Wu 1 Xu Zhang 1 Xiaoli Zheng 1 Ruili Zhang 2 Qianqiu Wang 1
Affiliations

Affiliations

  • 1 Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, China.
  • 2 Department of Dermatology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China.
Abstract

Neurosyphilis, a neurological manifestation of syphilis, is closely related to neuroinflammation. Autophagy, a fundamental cellular mechanism that mediates the degradation of intracellular components, plays a crucial role in immune regulation and inflammation. Microglia, resident immune cells in the brain, are central to these processes. However, the interplay between Autophagy and neuroinflammation in the context of neurosyphilis remains poorly understood. In this research, the recombinant Treponema pallidum flagellin, FlaB3, was constructed to treat human microglia clone 3 (HMC3) cells and HMC3 cells in which TLR4 (Toll-like Receptor 4) had been knocked down. We discovered that FlaB3 promotes IL-6 and IL-8 secretion through the TLR4 pathway. We also observed that FlaB3 regulates the expression of autophagy-related proteins Beclin1, LC3B, and p62 via the TLR4/PI3K/Akt/mTOR pathway, thereby inhibiting Autophagy and autophagic flux in HMC3 cells. Subsequently, we discovered that the concentration of soluble amyloid β1-42 (Aβ1-42) was decreased in the cerebrospinal fluid of neurosyphilis patients. Immunofluorescence analysis further revealed that FlaB3 suppresses the degradation of Aβ by autophagosomes in HMC3 cells. Additionally, treatment with the Autophagy activators Rapamycin and LY294002 decreased the levels of IL-6 and IL-8 secretion, indicating that Autophagy modulates inflammation in HMC3 cells. In summary, our study demonstrates that FlaB3 promotes inflammation in HMC3 cells by inhibiting Autophagy. This inhibition also impedes Aβ degradation, providing new insights into the pathogenesis of neurosyphilis.

Keywords

amyloid-β; autophagy; flagellin FlaB3; neuroinflammation; neurosyphilis.

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