Shinjo, T. | Search bioRxiv

bioRxiv2021

Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25-Nrf2 signaling

Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.

immunology↗

bioRxiv2020

Selective and controlled myelin formation by individual interfascicular oligodendrocytes in the mouse corpus callosum

Single oligodendrocytes produce myelin sheath around multiple axons in the central nervous system. Interfascicular oligodendrocytes (IOs) in the white matter are aligned in rows and facilitate nerve conduction, but their detailed morphologies remain largely unknown. In the present study, we three-dimensionally reconstructed seven IOs in a row in the murine corpus callosum using serial block face-scanning electron microscopy (SBF-SEM). These morphologically polarized IOs extended a thick process with numerous branches from the cytoplasm-rich part of the cell and formed myelin sheaths preferentially around distant axons. The multiple branched processes of each IO myelinated multiple axons having similar diameters with restricted myelin thicknesses, indicating that individual IOs have their own myelination profiles even on distinct target neurons. Consistent with the finding, the IOs transduced and visualized with the rabies viral vector expressing GFP showed statistically significant variations in the myelination patterns. We further reconstructed the sheath immediately adjacent to those derived from the seven IOs; the thicknesses of both sheaths were significantly correlated despite emanating from different IOs. These results proposed a rule that myelination by individual IOs, regulated by interaction with ensheathed axons, is selective in specific axons and at the same time orchestrated at the whole cell level. Main pointsCallosal oligodendrocytes form myelin sheaths preferentially around distant axons. Each oligodendrocyte myelinate multiple axons having similar diameters with restricted myelin thicknesses. The thicknesses of adjacent myelin sheaths are similar.

neuroscience↗