Exposure to chronic hypoxia (CH: 3-28 days @ 380 Torr) induces adaptation in mammalian carotid body such that following CH an acute hypoxic challenge elicits an abnormally large increase in carotid sinus nerve (CSN) impulse activity. The current study examines the hypothesis that CH initiates an immune response in the carotid body, and that chemoreceptor hyperexcitability is dependent on the expression and action of inflammatory cytokines. CH resulted in a robust invasion of ED1+ macrophages which peaked on day 3 of exposure. Gene expression of pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor- (TNF), and the chemokine, monocyte chemoattractant protein-1 (MCP-1), was increased more that 2-fold after 1 day of hypoxia, followed by a 2-fold+ increase in interleukin-6 (IL) on day 3. After 28 days of CH, IL-6 remained elevated >5-fold, whereas expression of other cytokines recovered to normal levels. Cytokine expression was not restricted to immune cells. Studies of cultured type I cells harvested following 1 day of in vivo hypoxia showed elevated transcript levels of inflammatory cytokines. In situ hybridization studies confirmed expression of IL-6 in type I cells, and also showed that CH induces IL-6 expression in supporting type II cells. Concurrent treatment of CH rats with anti-inflammatory drugs (ibuprofen or dexamethasone) blocked immune cell invasion and severely reduced CH-induced cytokine expression in carotid body. Drug treatment also blocked the development of chemoreceptor hypersensitivity in CH animals. Our findings indicate that chemoreceptor adaptation involves novel neuroimmune mechanisms which may alter the functional phenotypes of type I cells and chemoafferent neurons.