HIF-1α regulated GLUT1-mediated glycolysis enhances Treponema pallidum-induced cytokine responses

Syphilis, caused by Treponema pallidum (Tp), represents a significant public health challenge. The clinical manifestations of syphilis are attributed to local inflammatory responses induced by Tp, notably monocyte infiltration into local lesions and the secretion of inflammatory cytokines. However, the mechanisms driving cytokine production in response to Tp infection remain largely unknown. Given that increased glycolysis is associated with inflammatory responses, we aimed to investigate the role of glycolysis in Tp-induced secretion of inflammatory cytokines. In this study, we found that Tp promotes the secretion of inflammatory cytokines IL-6, IL-8, and CCL2 from monocytes while enhancing glycolysis through increased GLUT1 plasma membrane expression and glucose uptake. Importantly, inhibiting glycolysis and GLUT1 reduced the Tp-induced secretion of monocyte inflammatory cytokines. Additionally, Tp significantly increased HIF-1α expression and induced its nuclear translocation, thereby promoting glycolysis by upregulating the expression of GLUT1 and LDHA glycolytic enzymes. Knockdown of HIF-1α inhibits Tp-induced monocyte cytokine secretion, highlighting the crucial role of HIF-1α-mediated glycolysis in the cytokine response to Tp. Also, expression of HIF-1α and an increase in glycolysis were confirmed in patients with syphilis. In conclusion, we demonstrated that HIF-1α-regulated GLUT1-mediated glycolysis enhances inflammatory cytokine secretion following Tp infection. Our findings not only elucidate the mechanism of glycolysis in Tp-induced inflammatory responses in monocytes but also contribute to the development of a potential biomarker in syphilis diagnosis and treatment.