Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia[1][1]-[15][2]. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia[16][3]-[20][4]. 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, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-6[1][1]-[5][5],[15][2],[18][6],[21][7]-[23][8], leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an 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 of Gfral-expressing AP neurons also ameliorates the cancer-associated 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-associated cachexia. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-15 [3]: #ref-16 [4]: #ref-20 [5]: #ref-5 [6]: #ref-18 [7]: #ref-21 [8]: #ref-23