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Neuroimmune axis of cardiovascular control: mechanisms and therapeutic implications

Abstract

Cardiovascular diseases (CVDs) make a substantial contribution to the global burden of disease. Prevention strategies have succeeded in reducing the effect of acute CVD events and deaths, but the long-term consequences of cardiovascular risk factors still represent the major cause of disability and chronic illness, suggesting that some pathophysiological mechanisms might not be adequately targeted by current therapies. Many of the underlying causes of CVD have now been recognized to have immune and inflammatory components. However, inflammation and immune activation were mostly regarded as a consequence of target-organ damage. Only more recent findings have indicated that immune dysregulation can be pathogenic for CVD, identifying a need for novel immunomodulatory therapeutic strategies. The nervous system, through an array of afferent and efferent arms of the autonomic nervous system, profoundly affects cardiovascular function. Interestingly, the autonomic nervous system also innervates immune organs, and neuroimmune interactions that are biologically relevant to CVD have been discovered, providing the foundation to target neural reflexes as an immunomodulatory therapeutic strategy. This Review summarizes how the neural regulation of immunity and inflammation participates in the onset and progression of CVD and explores promising opportunities for future therapeutic strategies.

Key points

  • The main routes of communication between the brain and the cardiovascular system are the brain circumventricular organs, the autonomic nervous system and the hypothalamus–pituitary–adrenal axis.

  • Immune organs are densely innervated by the peripheral nervous system.

  • The nervous system might contribute to cardiovascular disease either directly through innervation of the cardiovascular system or indirectly by influencing the immune responses involved in cardiovascular pathology.

  • Innovative approaches that are based on bioelectronic or ultrasound-driven modulation of immune organs are emerging options for the treatment of cardiovascular disorders.

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Fig. 1: Routes of communication between the brain and peripheral organs.
Fig. 2: Neural control of immune organs.
Fig. 3: Neuroimmune interactions contribute to the onset of cardiovascular risk factors and progression of cardiovascular disease.
Fig. 4: Emerging clinical perspectives for neuroimmune modulation in cardiovascular disease.

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Acknowledgements

Work in the author’s laboratory is supported by the European Research Council (ERC-StG-GA759921), the European ERA-CVD Joint Transnational Call 2018 (NEMO-IMMUNEagainstHF) and 2019 (Gut-Brain-Immune-HHD), the Italian Ministry of University and Research (FARE-MIUR-R18RLRPS2R), and the Italian Ministry of Health (Ricerca Corrente). The author thanks G. Lembo, M. Perrotta and L. Carnevale from the laboratory for helpful discussion and inspiration for preparing the figures before submission.

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Glossary

Angiotensin II

A biologically generated peptide hormone of the renin–angiotensin–aldosterone system, with potent vasoconstrictor effects and signalling functions, also used to induce hypertension in experimental models.

Optogenetics

A technology that uses light to control and sense neurons that have been genetically modified to express channelrhodopsin 2, a light-gated cation channel.

Deoxycorticosterone acetate

(DOCA). A mineralocorticoid that is used together with salt in drinking water in a well-established preclinical model to recapitulate moderate-to-severe, salt-sensitive hypertension.

6-Hydroxydopamine

A hydroxylated analogue of dopamine used as a neurotoxic synthetic organic compound that can selectively destroy dopaminergic and noradrenergic neurons in the brain.

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Carnevale, D. Neuroimmune axis of cardiovascular control: mechanisms and therapeutic implications. Nat Rev Cardiol 19, 379–394 (2022). https://doi.org/10.1038/s41569-022-00678-w

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