Macrophage-glia interactions regulate immune-damage to enteric neurons during West Nile virus infection [4]

Functional gastrointestinal (GI) tract disorders affect a substantial proportion of the global population and are often preceded by intestinal infections that cause injury to enteric neurons and glia through unrestrained immune responses. However, the mechanisms that limit infection-induced inflammation and protect the enteric nervous system remain poorly understood. Here, we investigated neuron-glia-macrophage interactions after West Nile virus (WNV) infection, a model neurotropic virus that causes GI tract dysmotility via injury of enteric neurons through a T cell-mediated cytolytic mechanism. In response to WNV infection, resident muscularis macrophages upregulate antiviral, proinflammatory, and immunomodulatory genes. However, pharmacological depletion of resident macrophages did not affect viral burden in the GI tract, but rather reshaped the enteric glial response to WNV, resulting in excessive production of T cell and neutrophil chemoattractants. This amplified recruitment of immune cells worsened enteric neuronal injury. Together, our findings identify resident muscularis macrophages as key regulators of glia-driven inflammation during enteric viral infection and reveal their role in protecting enteric neurons from immune-mediated damage. Overall design: Translating ribosomal affinity purification (TRAP) of the muscularis externa of West Nile virus (WNV) Plp1CreER;NuTRAP mice treated with either anti-CSF1R (to deplete resident macrophages) or isotype control antibody was performed at 6 days post infection to identify factors regulating response of enteric glia in distal part of small intestine to WNV in the absence of resident macrophages. Isolated immunopreciptated ribosome-bound mRNA from enteric glia was used for high-throughput sequencing.