Spleen-to-Liver Signals Control Systemic Inflammation
Spleen-to-Liver Signals Control Systemic Inflammation

Spleen-to-Liver Signals Control Systemic Inflammation

In rats, the spleen directs a cytokine surge that drives system-wide inflammation, but it is not, as once believed, the main producer of the chemical messenger.

Ruth Williams
Apr 29, 2021

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Contrary to established dogma, the spleen is not the principal source of the pro-inflammatory cytokine called tumor necrosis factor (TNF), which drives the sort of system-wide inflammation seen in sepsis. A paper in Science Signaling last week (April 20) reports that the liver and lungs of rats produce more TNF than the spleen does, but the spleen remains the master regulator, of the liver at least, instructing the nearby organ, via lipid signals, on how much TNF to make.

“This is a very interesting article reporting that the spleen enhances TNFα production in the liver. . . [and] showing the intermodulation between organs and the complex mechanisms of physiologic interplay,” Duke University’s Luis Ulloa, who studies immunobiology and was not involved in the paper, writes in an email to The Scientist.

“It’s a fascinating manuscript,” adds immunologist Henrique Serezani of Vanderbilt University in an email to The Scientist. It has “opened new avenues to understand the relative role of soluble inflammatory mediators in interorgan communication. 

The spleen might be one of the least appreciated organs in the body, spending its time performing the rather janitorial tasks of clearing out old and damaged red blood cells, recycling their iron, and keeping a stock of new red blood cells ready in case they’re needed. It’s even possible to live fairly well without a spleen. But, in times of infection, this organ’s status demands higher regard. It detects pathogens in the blood, produces immune cells and antibodies to fight them, and, has long been thought of as the number one source of the critical proinflammatory cytokine TNF during systemic infections. That is, until neuroimmunologist Alexandre Steiner of the University of São Paulo and colleagues discovered that actually, no, it isn’t.

The basis for the spleen’s title as TNF top producer had been the finding that removing the organ from an animal prevents the surge in TNF normally seen during massive microbial infections (caused by gut perforations, for example) or following intravenous injections with lipopolysaccharides (LPS)—bacterial molecules that trigger inflammation. But as Steiner’s team now shows, in rats with intact spleens, LPS-induced production of TNF in the lungs and liver actually exceeds that of the spleen.

To explain the splenectomy results, Steiner reasoned that the spleen might signal to other organs around the body to also produce TNF. With the spleen gone, the signal would therefore be gone too. In this latest study, his team tested this idea. They found that removing the spleen from rats reduced LPS-induced Tnf gene expression in the liver, but that hepatectomy (liver removal) did not reduce Tnf gene expression in the spleen. The result pointed to the existence of that one-way signal to ramp up TNF production.

To confirm the presence of such a signaling molecule, the team incubated liver macrophages, a major TNF-producing cell type, in media previously used to culture splenic macrophages—meaning the broth would contain substances the spleen macrophages had released—and, sure enough, this conditioned media boosted LPS-induced TNF production in the liver cells. 

The team went on to perform mass spectrometry experiments on plasma samples from splenectomized and non-splenectomized rats that had or had not received an intravenous LPS injection. The idea was to search for molecules that were produced by the spleen in response to LPS and that would therefore be abundant in the non-splenectomized, LPS-treated animals but not the others. This led to the identification of the lipid leukotriene B4—a known inflammatory molecule—as the likely spleen signal. And, when cultured liver cells were treated with the lipid, it induced TNF production in a dose-dependent manner, an effect that was blocked by leukotriene B4 inhibitors. The lipid had no effect on TNF production by splenic macrophages themselves, confirming its unidirectional activity.

While the precise mechanism underlying leukotriene B4’s effects on liver macrophages has yet to be determined, these results are “important findings highlighting the value of a systems or biological approach to experimentation not possible with reductionist approaches,” immunologist Kevin Tracey of the Feinstein Institutes for Medical Research who also did not participate in the research writes in an email to The Scientist. In other words, studies at the inter-organ or whole-animal level can sometimes provide insights that cell or molecular experiments cannot.

Furthermore, by “delineating communications mechanisms between the spleen and liver,” Serezani writes, the findings “could unlock new therapeutic opportunities to treat infectious and noninfectious diseases.”  

And therapies are desperately needed, says Steiner, because “the immune response is a double-edged sword.” On the one hand, cytokine signals including TNF are essential for a swift and strong response to an invading pathogen, but too strong a response for too long can be damaging to the host. Indeed, sepsis, which is an over-exuberant immune response, is responsible for millions of deaths worldwide each year, Steiner says.  

The ultimate hope, Steiner adds, is that by knowing the key molecules regulating such responses, researchers will be able to develop medicines to “fine tune the immune response . . . in a personalized way.”

M.T. Fonseca et al., “A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation,” Sci Signal, 14:eabb0969, 2021.