Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation

• Published in: Brain, behavior, and immunity behavior, and immunity, 2025-01, Vol.123, p.886-902
• Main Authors: Li, Xiaolin, Zhu, Xinxia, Diba, Parham, Shi, Xuan, Vrieling, Frank, Jansen, Fleur A.C., Balvers, Michiel G.J., de Bus, Ian, Levasseur, Peter R., Sattler, Ariana, Arneson-Wissink, Paige C., Poland, Mieke, Witkamp, Renger F., van Norren, Klaske, Marks, Daniel L.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Hypothalamus - metabolism; Inflammation - metabolism; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms - metabolism; NF-kappa B - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2024.11.002

•Tumor-derived Prostaglandin E2 (via COX-2) and host gut-originated LPS synergistically amplify hypothalamic inflammation in vitro and in vivo.•Prostaglandin E2 directly induces hypothalamic inflammation through EP4 receptor activation.•Prostaglandin E2 enhances hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived PAMPs.•Tumor-specific COX-2 knockout attenuates hypothalamic inflammation and improves survival during cancer. Hypothalamic inflammation often coincides with cancer and cachexia-anorexia. Prior work established the significance of tumor-derived inflammatory factors in triggering hypothalamic inflammation, yet the precise mechanisms remained elusive. Here, we demonstrate that prostaglandin E2 (PGE2), produced in the tumor via cyclooxygenase-2 (COX-2), plays a pivotal role in this context. PGE2 itself directly exerts pro-inflammatory effects on the hypothalamus through the EP4 receptor, while also augmenting hypothalamic inflammation via NF-κB pathways in the presence of host gut-derived pathogen-associated molecular patterns (PAMPs). In tumor-bearing mice, we confirm this synergistic interaction between tumor-derived COX-2/PGE2 and host-derived lipopolysaccharide (LPS) in amplifying hypothalamic inflammation. Supporting this mechanism we find that the tumor-specific knockout of COX-2 attenuates hypothalamic inflammation and improves survival in mice. Together, these findings highlight the mechanisms of tumor-associated COX-2 in fuelling hypothalamic inflammation. They also emphasize the potential of tumor-specific COX-2 inhibition and targeting gut permeability as a novel therapeutic strategy for improving clinical outcomes in cancer patients.