Modulation of leukotriene B₄ receptor 1 signaling by receptor for advanced glycation end products (RAGE)

Leukotriene B₄ (LTB₄) receptor 1 (BLT1), a high-affinity GPCR for LTB₄, plays important roles in acute and chronic inflammatory diseases. Although the LTB₄-BLT1 axis is known to promote inflammation, no studies have defined the binding proteins that modulate LTB₄-BLT1 signaling. In this study, the receptor for advanced glycation end products (RAGE) interacted with BLT1 in human cervical epithelial HeLa cells. RAGE increased LTB₄-BLT1-dependent ERK phosphorylation and inhibited LTB₄-BLT1-dependent activation of NF-κB and up-regulation of proinflammatory cytokines and chemokines. RAGE-dependent inhibition of NF-κB was blunted by treatment with an MEK inhibitor, suggesting that RAGE suppresses LTB₄-BLT1-dependent NF-κB signaling by enhancing the MEK-ERK pathway. Meanwhile, in a chemotaxis assay of mouse bone marrow-derived neutrophils, the velocity of LTB₄-dependent neutrophil migration was attenuated by soluble RAGE, which is an inhibitory decoy protein for RAGE signaling, in a dose-dependent manner (0.2–5 μg/ml), or by RAGE deficiency. Furthermore, both LTB₄-dependent ERK phosphorylation in neutrophils and LTB₄-dependent neutrophil accumulation in a murine peritonitis model were significantly attenuated in RAGE-deficient mice compared with C57BL/6J wild-type mice, indicating that RAGE potentiates LTB₄-dependent neutrophil migration by enhancing ERK phosphorylation. Our results demonstrate that RAGE interacts with BLT1 and modulates LTB₄-BLT1 signaling through potentiation of the MEK-ERK pathway.—Ichiki, T., Koga, T., Okuno, T., Saeki K., Yamamoto, Y., Yamamoto, H., Sakaguchi, M., Yokomizo, T. Modulation of leukotriene B₄ receptor 1 signaling by receptor for advanced glycation end products (RAGE). FASEB J. 30, 1811–1822 (2016). www.fasebj.org.