A macrophage-mediated TNFa signaling axis within peripheral nerves is required for initiation of autoimmune peripheral neuropathy. A macrophage-mediated TNFa signaling axis within peripheral nerves is required for initiation of autoimmune peripheral neuropathy

Immune cells infiltrate peripheral nerves after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in autoimmune neuropathies (e.g., GBS and CIDP), immune cells are pro-inflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may therefore reveal new therapeutic targets for switching immune cells from an inflammatory to a reparative state. In an autoimmune neuropathy mouse model, we used single cell transcriptomic studies of sciatic nerves to discover a TNFα signaling axis induced by IFNγ. Macrophages were the main source of TNFα, and autocrine TNFα signaling upregulated multiple autoimmunity-associated genes (e.g., Clec4e; Marcksl1; Cxcl1; Cxcl10). TNFα signaling was absent in nerve macrophages after injury, suggesting that TNFα signaling defines autoimmunity-associated pro-inflammatory macrophages. Finally, TNFα/TNFα signaling blockade ameliorated PNS autoimmunity development, which provides pre-clinical evidence that the TNFα axis may be effectively targeted to resolve inflammatory neuropathies. Overall design: Examination of single-cell profiles of immune cells in NOD.AIRE GW/+ and wild-type sciatic nerves