Diverse cell types establish a pathogenic immune environment in peripheral neuropathy

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Neuroinflammation is crucial in neurodegenerative diseases.
• SARM1 (the central executioner of axon degeneration) is activated by NMNAT2 mutations in a rare congenital neuropathy.
• Macrophages play a key role in this sarmopathy model.

Purpose of the Study:

• Investigate the impact of chronic SARM1 activation on the peripheral nerve environment.
• Identify SARM1-dependent neuroimmune mechanisms in peripheral neuropathy.

Main Methods:

• Single cell/nucleus RNA-sequencing (sc/snRNA-seq) of peripheral nerves.
• Analysis of immune cell populations (macrophages, T lymphocytes).
• Assessment of transcriptional changes in nerve-resident cells.

Main Results:

• Chronic SARM1 activation expanded immune cells (macrophages, T cells) and repair Schwann cells.
• Fibroblasts increased chemokine and complement expression, aiding immune recruitment.
• An Il1b+ macrophage subpopulation showed enhanced phagocytosis and T cell activation markers.
• T cell depletion rescued motor deficits in the sarmopathy model.

Conclusions:

• Chronic SARM1 activation profoundly alters the peripheral nerve milieu.
• SARM1-dependent neuroinflammation, involving macrophages and T cells, drives neuropathy.
• Immunomodulatory therapies are promising for SARM1-dependent peripheral neurodegenerative diseases.