期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：4
DOI：10.1073/pnas.2114406119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
GBS and CIDP are autoimmune disorders of the PNS that can be debilitating and even life threatening. Current therapies, which include corticosteroids and intravenous gammaglobulin, have poorly defined mechanisms of action and are ineffective in a fraction of patients. To identify more specific therapeutic targets, we used single-cell RNA sequencing to analyze immune cells in nerves during autoimmune attack. This analysis revealed a previously unappreciated TNFα cell–cell communication pathway that recruits and activates multiple immune cell types. Moreover, we show that TNF-α signaling is an essential feature of PNS autoimmunity, since ablating TNF-α signaling protects against disease. These findings suggest that anti–TNF-α agents, which are already used to treat other inflammatory diseases, should be considered for inflammatory neuropathies.
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 Barré 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-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α 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-α signaling induced macrophage expression of multiple genes (
Clec4e,
Marcksl1,
Cxcl1, and
Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.
