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Area postrema neurons mediate interleukin-6 function in cancer cachexia. | LitMetric

AI Article Synopsis

  • * Researchers discovered that the area postrema (AP) in the hindbrain is key for how peripheral IL-6 affects the brain, as elevated IL-6 levels can activate neurons in this area, resulting in increased activity and excitatory synaptic transmission.
  • * Targeting IL-6 in the brain with an anti-IL-6 antibody or using CRISPR techniques to suppress IL-6 receptors in AP neurons can reduce cachexia symptoms and extend lifespan in tumor-bearing mice, highlighting a potential therapeutic target.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144211PMC
http://dx.doi.org/10.1038/s41467-024-48971-1DOI Listing

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