2. Academic Validation
  3. Treponema pallidum protein Tp47 upregulates TNFAIP3 to promote microglia-mediated angiogenesis through the SOCS3/IL6 signaling pathway

Treponema pallidum protein Tp47 upregulates TNFAIP3 to promote microglia-mediated angiogenesis through the SOCS3/IL6 signaling pathway

  • Microb Pathog. 2026 Jan:210:108172. doi: 10.1016/j.micpath.2025.108172.
Lin Xie 1,  Feng-Qian Ma 1,  Meng-Xue Zheng 1,  Ya Yan 1,  Ruo-Ying Wang 1,  Tian-Ci Yang 2,  Li-Li Liu 3
Affiliations

Affiliations

  • 1 Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, 361004, China.
  • 2 Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, 361004, China; Xiamen Clinical Laboratory Quality Control Center, Xiamen, Fujian Province, China. Electronic address: [email protected].
  • 3 Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, 361004, China; Xiamen Clinical Laboratory Quality Control Center, Xiamen, Fujian Province, China. Electronic address: [email protected].
PMID: 41224156 DOI: 10.1016/j.micpath.2025.108172
Abstract

Background: Neurosyphilis, resulting from Treponema pallidum (T. pallidum) invasion of the central nervous system, is characterized by neuroinflammation and abnormal angiogenesis. The T. pallidum protein Tp47 has been shown to modulate microglial function, however, its specific role in neurovascular remodeling remains to be elucidated.

Methods: To explore Tp47-mediated neurovascular interactions, Human Microglia Clone 3 (HMC3) cells and human umbilical vascular endothelial cells (HUVECs) were used in the Transwell and conditioned medium assays to assess microglial migration and endothelial tube formation. Cytokine levels were measured by chemiluminescence Immunoassay, and key inflammatory mediators identified by RNA Sequencing were validated by Western blot. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) knockdown in HMC3 cells was performed using specific siRNA, and angiogenic features in HUVECs were evaluated following exposure to microglial conditioned media, recombinant IL6, or neutralizing antibodies against Tp47 or IL6.

Results: Tp47 significantly enhanced HMC3 migration toward HUVECs and promoted endothelial network formation. Cytokine profiling and RNA-seq analyses placed IL6 and TNFAIP3 at the core of the Tp47-induced inflammatory response in microglia. Tp47 upregulated TNFAIP3, which suppressed the suppressor of cytokine signalling-3 (SOCS3) and resulted in increased IL6 secretion. Knockdown of TNFAIP3 restored SOCS3 levels, reduced IL6 output, and attenuated the pro-angiogenic activity of microglial conditioned media. Neutralization of Tp47 or IL6 abolished angiogenesis, while exogenous IL6 alone recapitulated it.

Conclusion: The T. pallidum protein Tp47 promotes IL6-driven angiogenesis by upregulating TNFAIP3 and suppressing SOCS3, linking microglial inflammation to neurovascular changes in neurosyphilis.

Keywords

Angiogenesis; IL6; SOCS3; TNFAIP3; Tp47; Treponema pallidum.

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