Treponema pallidum induces pro-inflammatory cytokine secretion in macrophages and macrophage-endothelial co-cultures

Syphilis, caused by the extracellular bacterium <i>Treponema pallidum</i> ssp. <i>pallidum</i>, is a multi-stage and systemic infection that is lifelong in the absence of treatment. Two host cell types that frequently encounter <i>T. pallidum</i> during infection are endothelial cells and macrophages; treponemes disseminate through the vasculature and cross the blood-brain and placental barriers by traversing endothelial cell barriers, and macrophages are known to be critical for clearance of <i>T. pallidum.</i> Despite the importance of macrophages in treponemal clearance and endothelial cells in treponemal dissemination, a comprehensive understanding of the cytokines secreted by <i>T. pallidum</i>-exposed macrophages in the presence and absence of endothelial cells has not yet been achieved. To address this knowledge gap, we conducted time-course cytokine secretion profiling of macrophage-differentiated THP-1 cells alone and in co-culture with human brain microvascular endothelial cells. These experiments revealed reduced IL-8 secretion and increased secretion of RANTES, soluble ICAM-1, IL-1β, MCP-1, GM-CSF, TNF, and IL-6 in <i>T. pallidum</i>-exposed macrophage monocultures and macrophage-endothelial cell co-cultures compared to the same culture conditions in the absence of <i>T. pallidum</i>. These investigations enhance our understanding of macrophage-mediated, <i>T. pallidum</i>-focused innate immune responses occurring at endothelial sites. Further, this study provides insight into pro-inflammatory mechanisms elicited after exposure to this pathogen that may contribute to endothelial junction disruption, <i>T. pallidum</i> dissemination, and syphilis symptoms.