Sarm1/Myd88-5 Regulates Neuronal Intrinsic Immune Response to Traumatic Axonal Injuries

Cell Rep. 2018 Apr 17;23(3):716-724. doi: 10.1016/j.celrep.2018.03.071.

Abstract

Traumatic injuries can trigger inflammatory reactions, leading to profound neuropathological consequences. However, the immune capacity of neurons, distinct from that of immune cells or glial cells, in response to traumatic insults remains to be fully characterized. In this study, we demonstrate that neurons can detect, cell autonomously, distant axonal damage, resulting in rapid production of a specific collection of cytokines and chemokines. This neuronal immune response appears spatially and temporally separated from injury-induced axon degeneration. We then identify through the genetic screen that this immune response is regulated by TIR-domain adaptor Sarm1/Myd88-5. We further show that Sarm1 functions through the downstream Jnk-c-Jun signal, and blockage of this Sarm1-Jnk-c-Jun pathway effectively abolishes the recruitment of immune cells to injury-afflicted neural tissues. We therefore uncover the key function of the Sarm1 signaling pathway, independent of its known role in axon degeneration, in the neuronal intrinsic immune response to traumatic axonal injuries.

Keywords: Sarm1; neuroinflammation; neuronal intrinsic immune response; traumatic injuries.

MeSH terms

  • Animals
  • Armadillo Domain Proteins / deficiency
  • Armadillo Domain Proteins / genetics*
  • Axons / metabolism*
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Neurons / cytology
  • Neurons / immunology
  • Neurons / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sciatic Nerve / injuries*
  • Signal Transduction

Substances

  • Armadillo Domain Proteins
  • Chemokines
  • Cytokines
  • Cytoskeletal Proteins
  • Myeloid Differentiation Factor 88
  • RNA, Small Interfering
  • SARM1 protein, mouse
  • JNK Mitogen-Activated Protein Kinases