A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation

Production of the proinflammatory cytokine tumor necrosis factor (TNF) must be precisely regulated for effective host immunity without the induction of collateral tissue damage. Here, we showed that TNF production was driven by a spleen-liver axis in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS). Analysis of cytokine expression and secretion in combination with splenectomy and hepatectomy revealed that the spleen generated not only TNF but also factors that enhanced TNF production by the liver, the latter of which accounted for nearly half of the TNF secreted into the circulation. Using mass spectrometry-based lipidomics, we identified leukotriene B₄ (LTB₄) as a candidate blood-borne messenger in this spleen-liver axis. LTB₄ was essential for spleen-liver communication in vivo, as well as for humoral signaling between splenic macrophages and Kupffer cells in vitro. LPS stimulated the splenic macrophages to secrete LTB₄, which primed Kupffer cells to secrete more TNF in response to LPS in a manner dependent on LTB₄ receptors. These findings provide a framework to understand how systemic inflammation can be regulated at the level of interorgan communication.