A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death

作者：Shigetoshi Yokoyama, Yan Cai, Miyuki Murata, Takeshi Tomita, Mitsuhiro Yoneda, Lei Xu, Aprile L. Pilon, Raúl E. Cachau, Shioko Kimura · 发表于：eLife · 年份：2018 · DOI：10.7554/elife.37854 · 被引用次数：74 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Immune Response and Inflammation

Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.