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

Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2114406119. doi: 10.1073/pnas.2114406119.


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.

Keywords: CIDP; TNF-α; autoimmunity; macrophages; peripheral nerve.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Autocrine Communication
  • Biomarkers
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Gene Expression Profiling
  • Inflammation Mediators / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Neuroinflammatory Diseases / drug therapy
  • Neuroinflammatory Diseases / etiology*
  • Neuroinflammatory Diseases / metabolism*
  • Neuroinflammatory Diseases / pathology
  • Paracrine Communication
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / etiology*
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / pathology
  • Polyendocrinopathies, Autoimmune / complications*
  • Polyendocrinopathies, Autoimmune / genetics
  • Receptors, Tumor Necrosis Factor / deficiency
  • Sciatic Nerve / immunology
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*


  • Antibodies, Monoclonal
  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha