Ruiz, D. M. | Search bioRxiv

bioRxiv2026

DRG meningeal tertiary lymphoid structures are regulated by B cells as a pronociceptive locus after peripheral nerve injury

B cell-derived IgG in the dorsal root ganglia (DRG) drives neuropathic pain after peripheral nerve injury (PNI), but the site of B cell organization is unclear. Here, PNI induced leukocyte clusters in the DRG meninges, enveloped by lymphatic endothelium and apposed to high endothelial venules. These clusters resemble tertiary lymphoid structures (TLSs) with germinal center-like features, including germinal center B cells and plasma cells, and follicular dendritic and follicular helper T cells. Single-cell RNA sequencing revealed enrichment of germinal center B cells in the DRG meninges after PNI. Germinal center B cells regulate TLS organization: TLSs were absent after deletion of Ezh2 from germinal center-experienced B cells. Intrathecal CD20 monoclonal antibody to locally deplete B cells also disrupted TLS organization. Conversely, intrathecal B cell transfer to B cell-deficient (muMT) mice was sufficient for TLS organization after PNI. Allodynia did not develop when TLS organization was disordered. Similar TLSs formed in pig DRG after tail docking and in human donors with chronic pain, where B cell receptor clonotype analysis confirmed functional maturity. Together, these data establish that germinal center B cells are required for TLS organization, and that disrupting this process abolishes the development of neuropathic pain after PNI.

neuroscience↗

bioRxiv2019

An insulin-stimulated proteolytic mechanism links energy expenditure with glucose uptake

Mechanisms to coordinately regulate energy expenditure and glucose uptake into muscle and fat cells are not well described. Insulin stimulates glucose uptake in part by causing site-specific endoproteolytic cleavage of TUG, which mobilizes GLUT4 glucose transporters to the cell surface. Here, we show that the TUG C-terminal cleavage product enters the nucleus, binds the transcriptional regulators PGC-1 and PPAR{gamma}, and increases oxidative metabolism and thermogenic protein expression. Muscle-specific genetic manipulation of this pathway impacts whole-body energy expenditure, independent of glucose uptake. The PPAR{gamma}2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1 and is itself susceptible to an Ate1 arginyltransferase -dependent degradation mechanism; binding of the TUG product confers Ate1-dependent stability upon PGC-1. We conclude that TUG cleavage coordinates energy expenditure with glucose uptake, that this pathway may contribute to the thermic effect of food, and that its attenuation may be important in obesity.

physiology↗