Sci Signal: Leukotriene-dependent spleen-liver axis drives TNF-a production in systemic inflammation

News from April 25, 2021 //---To achieve effective host immunity without causing collateral tissue damage, it depends on the precise regulation of the pro-inflammatory cytokine "Tumor Necrosis Factor (TNF)"
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In a recent study, the team of Alexandre A.
Steiner from the University of São Paulo in Brazil revealed the mechanism by which the spleen-liver axis drives TNF production in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS)
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The relevant results were published in the "Science Signaling" magazine
.

(Image source:this study, the authors first assessed the relative contribution of the spleen and liver to TNF production in a rat model of LPS-induced systemic inflammation, and whether there is an interdependence between these organs in the context of TNF production
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In response, the authors injected LPS from E.
coli O55:B5 or control saline intravenously into unanaesthetized male Wistar rats
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30 or 80 minutes after injection, spleen, liver and lung samples were collected for cytokine gene expression analysis
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The author evaluated gene expression by RT-PCR), and verified the accuracy of PCR by the yield of a single amplicon of the expected size of each target gene
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Compared with the spleen and liver, the expression of Tnf in the lung was the highest in rats injected with control saline
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In all organs tested 30 minutes after LPS injection, the expression of Tnf in the liver and spleen was at similar levels, but LPS significantly enhanced the expression of TNF in the lung
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80 minutes after LPS injection, there was no difference in Tnf expression between liver and spleen.
Although Tnf expression in the lung was still higher than that in the liver, the difference between these organs was no longer significant
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Regarding other cytokines, at least one time point after LPS, the expression of Il1b and Il10 in the liver and lung was higher than that in the spleen, while in the control group injected with saline, there was no difference in the expression of these cytokines among various organs
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(Figure 1, Analysis of cytokine production levels in various organs triggered by LPS stimulation)

Because the increase in gene expression is a key step in the production and secretion of cytokines, even if the secretion of IL-1β depends on the inflammasome, the increase in gene expression is a necessary condition
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Therefore, the above results indicate that the spleen is not the only source of pro-inflammatory factors, but the liver and lung should also be used as sources of inflammatory cytokines
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For cell-level analysis, the authors compared the expression and secretion of cytokines in resident macrophage cultures isolated from the spleen, liver, or lung
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The results showed that LPS stimulation resulted in a statistically significant increase in Tnf expression in all macrophages.
In terms of Tnf expression, the expression level of lung (alveolar) macrophages was second only to Kupffer cells
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The expression of Tnf in splenic macrophages is at least 250 times lower than that in Kupffer cells and at least 50 times lower than that in alveolar macrophages
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In order to directly assess the liver's contribution to LPS-induced cytokine production, the authors performed partial hepatectomy on mice before LPS stimulation
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The middle lobe and left lobe of the liver, which account for about 70% of the liver mass, were removed, while the right lobe and caudate lobe and their blood vessel connections were retained
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In order to avoid the risk of important liver function loss, the authors conducted experiments under anesthesia immediately after hepatectomy or control surgery in rats
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Compared with the control group, the plasma TNF surge effect induced by LPS was reduced by 32% in hepatectomy rats
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This reduction has nothing to do with the suppression of Tnf expression in the remaining organs (spleen and lung)
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Therefore, the decrease in plasma TNF caused by hepatectomy reflects the liver's own contribution to the production of this cytokine
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(Figure 2, Leukotriene regulates the spleen-liver axis communication and TNF production in rats)

In the end, the authors discovered that the leukotriene B4 (LTB4) secreted in the spleen is a key factor driving the production of TNF, and then revealed the role of the "spleen-liver axis" in regulating systemic inflammation
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The analysis of cytokine expression and secretion combined with splenectomy and hepatectomy showed that the spleen not only produces TNF, but also produces upstream factors that promote the secretion of TNF from the liver
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The results of lipidomics analysis based on mass spectrometry showed that leukotriene B4 (LTB4) is a messenger molecule in the spleen-liver axis
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LTB4 is essential for spleen-liver communication in vivo and humoral signal transmission between splenic macrophages in vitro and so on
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LPS stimulates spleen macrophages to secrete LTB4, so that Kupffer cells secrete more TNF in a LTB4 receptor-dependent manner in response to LPS
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These findings provide new ideas for further understanding how various organs communicate with each other to regulate systemic inflammation
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(Bioon.
com)

Original source: Monique T.
Fonseca, Eduardo H.
Moretti, Lucas MM et al.
, A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation.
Science Signaling  20 Apr 2021:
Vol.
14, Issue 679, eabb0969 DOI: 10.
1126/scisignal.
abb0969