Re-Analysis of Single-Nucleus Transcriptomics Reveals Diverse Dorsal Root Ganglia Macrophage Responses Following Peripheral Nerve Injury

An increasing amount of evidence points to an important role of macrophages in peripheral nerve injury (PNI) and associated pain. Peripheral nerve macrophages facilitate the regeneration, while dorsal root ganglia (DRG) macrophages might propagate the injury after a PNI. These differences might be explained by various in vivo models of PNIs or non-uniform methodologies to phenotype the macrophages. Unbiased methods to phenotype macrophages using single whole cell or nucleus transcriptomics have been rarely applied on PNIs outside the nerves themselves. Here, we compare the effects of the transection or crush of the sciatic nerve and spinal nerve transection on the DRG macrophage phenotypes utilizing a publicly available single-nucleus transcriptomic DRG dataset. Our results demonstrate that unique and time-dependent DRG macrophage gene expression profiles were produced by the three PNI models with particular macrophage clusters being enriched that were dependent on the severity of the neuronal injury score. PNI associated DRG macrophages were not purely anti- or pro-inflammatory. These results suggest that various functions of DRG macrophage subtypes are carefully orchestrated upon a PNI. These findings open a new avenue for studying the DRG macrophage subtypes in PNIs and encourage further unbiased phenotyping efforts to better understand their relevance in neuropathic pain.

Automated summary

Increasing evidence suggests that macrophages play an important role in peripheral nerve injury (PNI) and associated pain. Differences in in vivo models and methodologies may explain the variations between peripheral nerve macrophages and dorsal root ganglia (DRG) macrophages. Using single-nucleus transcriptomic analysis, this study compared the effects of sciatic nerve transection, spinal nerve transection, and nerve crush on DRG macrophage phenotypes. The findings demonstrate unique and time-dependent gene expression profiles of DRG macrophages in the different PNI models, suggesting a carefully orchestrated response of various DRG macrophage subtypes in PNI.