Area postrema neurons mediate interleukin-6 function in cancer cachexia

Qingtao Sun, Daniëlle Lisdonk, Miriam Ferrer, Bruno Gegenhuber, Melody Wu, Youngkyu Park, David A. Tuveson, Jessica Tollkuhn, Tobias Janowitz and Bo Li ()
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Qingtao Sun: Cold Spring Harbor Laboratory
Daniëlle Lisdonk: Cold Spring Harbor Laboratory
Miriam Ferrer: Cold Spring Harbor Laboratory
Bruno Gegenhuber: Cold Spring Harbor Laboratory
Melody Wu: Cold Spring Harbor Laboratory
Youngkyu Park: Cold Spring Harbor Laboratory
David A. Tuveson: Cold Spring Harbor Laboratory
Jessica Tollkuhn: Cold Spring Harbor Laboratory
Tobias Janowitz: Cold Spring Harbor Laboratory
Bo Li: Cold Spring Harbor Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia.

Date: 2024
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DOI: 10.1038/s41467-024-48971-1

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