In a recent article published in Nature, Jin and colleagues investigate the role of the body–brain axis in modulating peripheral immune responses. They demonstrate that this axis, which integrates peripheral immune signals with central nervous system responses via the vagus nerve, contributes to maintaining immune homeostasis and preventing inflammatory dysregulation.

A fundamental function of the central nervous system (CNS) is to maintain body homeostasis, i.e., to keep the functional parameters of each tissue within a pre-set range. To achieve this aim, the CNS constantly receives information from the external and internal environments. This constant influx of information is then centrally integrated and transformed into functional outputs which are transmitted to the periphery. This bidirectional communication between the periphery and the CNS is termed body–brain axis and is mediated by circulating factors and neural pathways. The body–brain axis enables the CNS not only to control the homeostasis of the cardiovascular, respiratory, gastrointestinal, musculoskeletal, renal, and neuroendocrine systems but also that of the immune system. This latter function is essential: both overshooting immune responses (e.g., autoimmune diseases or cytokine storms) or insufficient immune responses (e.g., immunodeficient conditions occurring in aging, cancer or chronic infections) can lead to irreversible tissue damage with consequent organ impairment and mortality. The notion that the brain and the immune system are interconnected via neural pathways has been since long proposed. Pioneering observations from Watkins, Niijima, and Tracey could identify the afferent and efferent arms of the vagus nerve as the “anatomical wires” (Fig. 1a).1,2,3 At a functional level, vagal nerve stimulation results in reduced inflammation, highlighting the relevance of the circuit.3 However, the precise mapping of the single neuronal elements mediating the body–brain connections and the overall logic of the system remained unknown.

Fig. 1: Body–brain axis controls the immune responses via the vagus nerve.
figure 1

a Schematic representation of the bidirectional communication between the body organs and the CNS mediated by the vagus nerve. The peripheral inputs are conveyed to the cNST (yin and yang symbols) localized in the brainstem and processed in the central autonomic network (arrow) before traveling back to the peripheral organs via the vagal efferent fibers. b Regulation of the inflammatory responses by the body–brain axis. Anti- or pro-inflammatory stimuli are conveyed to the cNST via TRPA1+ or CALCA1+ neurons, respectively. The integration of the signals results in an anti-inflammatory output. This figure was created with BioRender.com.

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The study by Jin and colleagues fills some of these gaps.4 The authors show that peripheral immune insults activate the body–brain axis, which, in turn, regulates the inflammatory response through a finely tuned feedback mechanism involving specific neuronal subpopulations of the vagus nerve and the brainstem. By combining detailed morphological analysis and functional interventions, the authors carefully dissect the essential elements of the circuit: the cytokines are identified as the system switch, and two distinct subsets of vagal neurons work as conductive pathways of either pro- or anti-inflammatory information. Finally, neuronal subpopulations in the caudal nucleus of the solitary tract (cNST) in the brainstem behave as a biological rheostat able to keep in check the amplitude of the peripheral immune response (Fig. 1b).

A key finding of this work is the identification of specific cNST neurons that are activated by cytokines produced by immune cells in response to peripheral immune challenges such as lipopolysaccharide (LPS), an essential component of the outer membrane of Gram-negative bacteria. These neurons are primarily glutamatergic and express the dopamine β-hydroxylase (Dbh) gene. At a functional level, the Dbh-expressing neurons turn out to be a key player in immune regulation: their silencing via a combination of the TRAP (targeted recombination in active populations) and the DREADD (designer receptors exclusively activated by designer drugs) systems, exacerbates LPS-mediated inflammation, while their activation suppresses it.

While searching for the mechanisms enabling the cNST neurons to receive information from the peripheral environment, the authors could unexpectedly identify distinct populations of vagal neurons that respond selectively to anti- or pro-inflammatory cytokines: TRPA1-expressing vagal neurons respond to anti-inflammatory cytokines, while CALCA-expressing neurons respond to pro-inflammatory cytokines. Both these conductive pathways relay information about peripheral inflammation to the brain, specifically to the cNST in the brainstem. However, the functional outcome differs: activating TRPA1-expressing neurons enhances the anti-inflammatory response, whereas activating CALCA-expressing neurons reduces the pro-inflammatory response. These findings highlight the specificity of the body–brain communication pathways and their role in fine-tuning immune responses.

The study’s findings could have significant therapeutic implications. By activating the Dbh-expressing neurons in this body–brain circuit, it could be possible to control peripheral inflammation. This approach harbors the potential to offer new avenues for treating a range of immune disorders, from autoimmune diseases to acute inflammatory conditions like cytokine storms. The researchers proved the principle in animal models of sterile sepsis and ulcerative colitis, where activation of the TRPA1+ vagal neurons or cNST neurons significantly improved survival and reduced pathology.

This study provides a detailed analysis of the neuroimmune circuits that regulate peripheral inflammation, underscoring the critical role of the body–brain axis in immune homeostasis. The detailed mechanistic insights and the demonstration of potential therapeutic interventions mark a significant advancement in our understanding of neuroimmune interactions. However, several questions remain open. A key area for further investigation is elucidating the precise mechanisms by which the sensing of peripheral inflammation by the vagus nerve is integrated into the brainstem and how the resulting output is further transmitted to the periphery to modulate the immune response. Furthermore, the molecular basis of the immune-neural interactions, in particular, how the vagal nerve terminations discriminate between the distinct cytokines, remains enigmatic. All these questions are required to be addressed in future studies in order to achieve a full understating of the body–brain axis in immune homeostasis.