An axon-T cell feedback loop enhances inflammation and axon degeneration

• Published in: Cell reports (Cambridge) 2024-02, Vol.43 (2), p.113721-113721, Article 113721
• Main Authors: Liu, Tingting, Wang, Huanhuan, Kutsovsky, Daniel Y., Iskols, Michael, Chen, Hongjie, Ohn, Christine Y.J., Patel, Nandan, Yang, Jing, Simon, David J.
• Format: Article
• Language: English
• Subjects: axon; axon degeneration; CP: Immunology; CP: Neuroscience; cytotoxic; feedback loop; gamma delta; neurodegeneration; neuroimmune; Sarm1; T cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113721

Inflammation is closely associated with many neurodegenerative disorders. Yet, whether inflammation causes, exacerbates, or responds to neurodegeneration has been challenging to define because the two processes are so closely linked. Here, we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons modulate skin inflammation through release of norepinephrine, which suppresses activation of γδ T cells via the β2 adrenergic receptor. Strong inflammatory stimulation—modeled by application of the Toll-like receptor 7 agonist imiquimod—causes progressive γδ T cell-mediated, Sarm1-dependent loss of these immunosuppressive sympathetic axons. This removes a physiological brake on T cells, initiating a positive feedback loop of enhanced inflammation and further axon damage. [Display omitted] •Development of a skin model to study the neuronal contribution to inflammatory axon loss•Adrenergic signaling is an axon-derived physiological brake limiting inflammation•Initial axon loss initiates a feedback loop that enhances inflammation and axon degeneration Liu et al. study the neuronal contribution to inflammatory neurodegeneration. They develop a model in skin, allowing independent manipulation of the inflammatory response and the survival of axons. Using this model, they define a positive feedback loop that governs the relationship between inflammation and axon degeneration.