The carotid body: A novel key player in neuroimmune interactions

Abstract

The idea that the nervous system communicates with the immune system to regulate physiological and pathological processes is not new. However, there is still much to learn about how these interactions occur under different conditions. The carotid body (CB) is a sensory organ located in the neck, classically known as the primary sensor of the oxygen (O₂) levels in the organism of mammals. When the partial pressure of O₂ in the arterial blood falls, the CB alerts the brain which coordinates cardiorespiratory responses to ensure adequate O₂ supply to all tissues and organs in the body. A growing body of evidence, however, has demonstrated that the CB is much more than an O₂ sensor. Actually, the CB is a multimodal sensor with the extraordinary ability to detect a wide diversity of circulating molecules in the arterial blood, including inflammatory mediators. In this review, we introduce the literature supporting the role of the CB as a critical component of neuroimmune interactions. Based on ours and other studies, we propose a novel neuroimmune pathway in which the CB acts as a sensor of circulating inflammatory mediators and, in conditions of systemic inflammation, recruits a sympathetic-mediated counteracting mechanism that appears to be a protective response.

Keywords: Carotid body; inflammation; neuroimmune interactions; neuroimmunomodulation; sympathetic nervous system.

Figure 1

The carotid body (CB) is a sensory organ located at the carotid bifurcation (33, 34, 36). The carotid sinus nerve (CSN), a branch of the IX nerve (glossopharyngeal nerve), provides the sensory innervation to the CB (34, 36). Pseudo-unipolar neurons with cell bodies located within the petrosal ganglion (PG) convey the sensory information from the CB to the central nervous system (32, 34, 36, 37). This sensory information is multimodal, since the CB is responsive not only to changes in the partial pressure of oxygen in the arterial blood, but also to changes in the levels of several circulating molecules (epinephrine, angiotensin II, cytokines, endothelin, glucagon like peptide-1, glucose, insulin, leptin, and sodium chloride) (, –, –, –64, 66, 67). Once depolarized, CB glomus cells release neurotransmitters, primarily ATP (39, 68). ATP binds to P2X2/P2X3 receptors in the afferent terminals of the CSN, generating action potentials which are propagated to the central nervous system (33, 38, 39, 68). Some of the ATP released by glomus cells is converted into adenosine by extracellular enzymes (NTPDase2,3 and ecto-5-nucleotidase) (38). Adenosine acts on A2a receptors on CSN afferent terminals, generating action potentials, and contributing to CB signaling to the central nervous system (–40). Other neurotransmitters (Others) such as acetylcholine, dopamine, and serotonin, have been also found to modulate CSN activity (33, 37, 39). CB, carotid body; CSN, carotid sinus nerve; IX nerve, glossopharyngeal nerve; PG, petrosal ganglion. Created with BioRender.com.

Figure 2

The CB is a sensor of peripheral inflammation and initiates a sympathetic-mediated anti-inflammatory response (26). 1: Elevated levels of TNF-α in the blood depolarizes CB glomus cells which widely express TNF-α receptors type I (, –73). Depolarization of CB glomus cells by TNF-α generates action potentials that propagate along axons within the CSN towards the brainstem (26). 2: The first central synapse of CB-originated axons occurs in the NTS, a major integrative brainstem region that receives the sensory information from peripheral organs and projects to several brainstem autonomic areas that control parasympathetic (DMV and NA) and sympathetic (RVLM) functions (32, 41, 46, 50, 52). 3: The TNF-α-induced activation of the CB-NTS-RVLM circuit increases the activity of the splanchnic sympathetic nerve which innervates the celiac ganglia, from where the splenic nerve originates and projects to the spleen, releasing norepinephrine (NE) (26). 4: The release of NE into the spleen reduces both splenic and plasmatic levels of TNF-α (26). CB, carotid body; CSN, carotid sinus nerve; DMV, the dorsal motor nucleus of the vagus; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; NE, norepinephrine; RVLM, rostral ventrolateral medulla; TNF-α, tumor necrosis factor-alpha. Created with BioRender.com.