Neurogenic inflammation has a well-recognized role in the regulation of the inflammatory response to a variety of noxious stimuli, including infections. At the lung level, this response is driven by the vagus nerve by means of modulation of parasympathetic pathways that can induce bronchospasm, mucus secretion, fluid extravasation and vasodilation. Besides parasympathetic vagal fibres, these noxious stimuli activate afferent sensory C-fibres and initiate defensive reflexes that ensure airway integrity; however, they can also release inflammatory neuropeptides such as substance P or calcitonin gene-related peptide (CGRP). In a recent Perspective (De Virgiliis, F. & Di Giovanni, S. Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19. Nat. Rev. Neurol. 16, 645–652 (2020))1, Francesco De Virgiliis and Simone Di Giovanni suggest a new strategy based on targeted modulation of vagal fibres to treat the life-threatening inflammatory reaction secondary to SARS-CoV-2 infection.
According to this novel therapeutic approach, based on the concept of the neuroimmune unit, patients who have undergone lung transplantation would be expected to have more adverse outcomes from COVID-19 owing to abolition of the anti-inflammatory effect of the vagus nerve by complete denervation of the lungs2 — including sensory, sympathetic and parasympathetic fibres — as a result of the transplant surgery. Consistent with the authors’ model, a recent multicentre study showed that, although lung transplant recipients have a clinical presentation of SARS-CoV-2 infection similar to that of the general population, they have a worse prognosis and higher mortality compared with non-transplanted patients3. However, lung transplantation also results in elimination of sensory C-fibres, which would block the release of inflammatory neuropeptides such as substance P and CGRP. This potential anti-inflammatory effect of lung denervation might contradict the authors’ model, unless there is crosstalk between vagal parasympathetic and sensory neuroimmune modulation.
Neurogenic inflammation is a key process in many inflammatory conditions and its modulation or blockade offers several treatment options. In this respect, surgical joint denervation is a well-recognized technique that improves osteoarthritic pain and synovial inflammation in the hand, where joints are densely innervated4,5. Nevertheless, in the more complex scenario of a denervated lung, the hypothetical equilibrium between vagal parasympathetic and sensory neuroimmune modulation should be taken into account, and further research is needed to comprehend the precise physiopathology and the role of both types of fibre in neurogenic lung inflammation. Vagal, sympathetic and sensory neurectomy following lung denervation could exacerbate COVID-19-associated inflammation through neuroimmune modulation but in theory could also exert anti-inflammatory effects secondary to disruption of inflammatory neuropeptide release6.
In summary, if denervation exerts anti-inflammatory effects in the joints, could it have similar effects in the lungs?
There is a reply to this letter by De Virgiliis, F. & Di Giovanni, S. Nat. Rev. Neurol. https://doi.org/10.1038/s41582-021-00485-w (2021).
De Virgiliis, F. & Di Giovanni, S. Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19. Nat. Rev. Neurol. 16, 645–652 (2020).
Zantah, M., Pandya, A., Marchetti, N., Jacobs, M. R. & Criner, G. J. Lung denervation and its effect on bronchial responsiveness following lung transplant surgery. Am. J. Respir. Crit. Care Med. 201, A2838 (2020).
Saez-Giménez, B. et al. COVID-19 in lung transplant recipients: a multicenter study. Am. J. Transplant https://doi.org/10.1111/ajt.16364 (2020).
Madsen, R. J., Stone, L. A., Knapp, J. B. & Solomon, J. S. Joint denervation in the digits: technique and patient satisfaction. Ann. Plast. Surg. 80, 27–31 (2018).
Kane, D. et al. Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint). Ann. Rheum. Dis. 64, 325–327 (2005).
O’Connor, T. M. et al. The role of substance P in inflammatory disease. J. Cell. Physiol. 201, 167–180 (2004).
The author declares no competing interests.
About this article
Cite this article
Arenas-Prat, J. Neuroimmune interactions and COVID-19 in lung transplant recipients. Nat Rev Neurol 17, 325 (2021). https://doi.org/10.1038/s41582-021-00484-x
Nature Reviews Neurology (2021)