Research ArticleImmunology

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

See allHide authors and affiliations

Science Signaling  20 Apr 2021:
Vol. 14, Issue 679, eabb0969
DOI: 10.1126/scisignal.abb0969

Inflamed from afar

The spleen is thought to be the major source of the proinflammatory cytokine TNF during systemic inflammation. However, Fonseca et al. found that the liver and lungs produced more TNF than did the spleen in response to LPS-induced systemic inflammation in rats. Experiments with splenectomized and hepatectomized animals and isolated tissue-resident macrophages showed that much of the spleen-dependent, LPS-induced increase in circulating TNF also depended on the production of TNF by Kupffer cells, the resident macrophages of the liver. Liver TNF production was enhanced in vivo and in vitro by leukotriene B4 (LTB4) released by the spleen. Together, these findings implicate LTB4 as a spleen-derived endocrine signal that promotes the hepatic production of TNF during 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.

View Full Text

Stay Connected to Science Signaling