Hypothalamic microglial IL-4 signaling mediates cancer-associated cachexia via sympathetic activation

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating metabolic syndrome characterized by progressive adipose tissue and skeletal muscle wasting. Emerging evidence implicates the central nervous system (CNS) as a key regulator of systemic catabolism and CAC progression. We identify interleukin-4 (IL-4) as a potential mediator of CAC by investigating its actions on hypothalamic neuroendocrine circuits. METHODS: We manipulated central IL-4 signaling in CAC mice through intracerebroventricular (ICV) delivery of anti-IL-4 antibody or recombinant IL-4. Hypothalamic cell type-specific IL-4 mechanisms were examined using CX3CR1-creERT2 mice for microglial IL-4 receptor (IL-4R) knockdown and pro-opiomelanocortin (POMC)-cre mice for chemogenetic modulation of POMC neurons. IL-4-induced neuroglial interactions were assessed using BV2 microglial and mHypoE-N1 hypothalamic neuronal cell lines and primary cells. RESULTS: Serum IL-4 and hypothalamic phospho-STAT6 were markedly elevated in tumor-bearing mice. Central IL-4 blockade significantly attenuated adipose tissue and muscle wasting, whereas ICV IL-4 administration reproduced cachectic phenotypes, establishing a causal role for brain IL-4 signaling in CAC. Central IL-4 drove adipose and muscle catabolism by activating two mechanistically distinct pathways: sympathetic nervous system and hypothalamic-pituitary-adrenal axis. IL-4R expression was predominantly localized to microglia, and IL-4-activated hypothalamic microglia engaged POMC neurons through proximity-dependent neuroglial interactions. Conditional knockdown of microglial IL-4R or chemogenetic suppression of POMC neurons markedly ameliorated tumor-induced cachexia, defining a central IL-4-microglia-POMC axis that contributes to the catabolic program in CAC. CONCLUSIONS: Hypothalamic IL-4 signaling contributes to CAC-associated tissue wasting and highlights microglial IL-4 signaling or POMC modulation as a potential mechanistic target for future therapeutic investigation.