Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barre Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory 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 role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-alpha (TNF-alpha) signaling axis that is induced by interferon-gamma and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-alpha signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-alpha signaling inducedmacrophage expression ofmultiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-alpha/TNF-alpha signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-alpha axis may be effectively targeted to resolve inflammatory neuropathies.

Automated summary

Immune cells play divergent roles in injury and autoimmunity. Understanding the phenotypes of these cells can reveal new therapeutic targets for inflammatory neuropathies. A TNF-alpha signaling axis is associated with autoimmune demyelination, and blocking this axis can ameliorate clinical symptoms.