Key points• The carotid body (CB) is the key oxygen sensor and governs the ventilatory response to hypoxia.• CB oxygen sensing and signalling gene expression is well described in animals whereas human data are absent.• Here we have characterized the human CB global gene expression in comparison with functionally related tissues and mouse CB gene expression.• We show that the human CB expresses oxygen sensing genes in common with mice but also differs on key genes such as certain K + channels. There is moreover increased expression of inflammatory response genes in human and mouse CBs in comparison with related tissues.• The study establishes similarities but also important differences between animal and human CB gene expression profiles and provides a platform for future functional studies on human CBs.Abstract The carotid body (CB) is the key oxygen sensing organ. While the expression of CB specific genes is relatively well studied in animals, corresponding data for the human CB are missing. In this study we used five surgically removed human CBs to characterize the CB transcriptome with microarray and PCR analyses, and compared the results with mice data. In silico approaches demonstrated a unique gene expression profile of the human and mouse CB transcriptomes and an unexpected upregulation of both human and mouse CB genes involved in the inflammatory response compared to brain and adrenal gland data. Human CBs express most of the genes previously proposed to be involved in oxygen sensing and signalling based on animal studies, including NOX2, AMPK, CSE and oxygen sensitive K + channels. In the TASK subfamily of K + channels, TASK-1 is expressed in human CBs, while TASK-3 and TASK-5 are absent, although we demonstrated both TASK-1 and TASK-3 in one of the mouse reference strains. Maxi-K was expressed exclusively as the spliced variant ZERO in the human CB. In summary, the human CB transcriptome shares important features with the mouse CB, but also differs significantly in the expression of a number of CB chemosensory genes. This study provides key information for future functional investigations on the human carotid body.

New Findings r What is the central question of this study?Data on human carotid body (CB) function are limited. The aim of this study was therefore to investigate whether the human CB releases acetylcholine, ATP or cytokines during hypoxia. r What is the main finding and its importance?Using human CBs, we demonstrate hypoxia-induced acetylcholine and ATP release, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. Moreover, the human CB releases cytokines upon hypoxia and expresses cytokine receptors as well as hypoxia-inducible factor proteins HIF-1α and HIF-2α in glomus cells, indicating their role in immune signalling and oxygen sensing, respectively, in accordance with previous animal data.Studies on experimental animals established that the carotid bodies are sensory organs for detecting arterial blood O 2 levels and that the ensuing chemosensory reflex is a major regulator of cardiorespiratory functions during hypoxia. However, little information is available on the human carotid body responses to hypoxia. The present study was performed on human carotid bodies obtained from surgical patients undergoing elective head and neck cancer surgery. Our results show that exposing carotid body slices to hypoxia for a period as brief as 5 min markedly facilitates the release of ACh and ATP. Furthermore, prolonged hypoxia for 1 h induces an increased release of interleukin (IL)-1β, IL-4, IL-6, IL-8 and IL-10. Immunohistochemical analysis revealed that type 1 cells of the human carotid body express an array of cytokine receptors as well as hypoxia-inducible factor-1α and hypoxia-inducible factor-2α. Taken together, these results demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. The finding that the human carotid body releases cytokines in response to hypoxia adds to the growing body of information M.J.F. and L.I.E. contributed equally to this paper.

In unique samples of the human CB, we here demonstrate presence of critical proteins in the oxygen-sensing and signaling cascade. Our findings demonstrate similarities to, but also important differences from, established animal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic drugs and human CB chemoreception.