RESUMEN
TFEB and TFE3 (TFEB/3), key regulators of lysosomal biogenesis and autophagy, play diverse roles depending on cell type. This study highlights a hitherto unrecognized role of TFEB/3 crucial for peripheral nerve repair. Specifically, they promote the generation of progenitor-like repair Schwann cells after axonal injury. In Schwann cell-specific TFEB/3 double knock-out mice of either sex, the TFEB/3 loss disrupts the transcriptomic reprogramming that is essential for the formation of repair Schwann cells. Consequently, mutant mice fail to populate the injured nerve with repair Schwann cells and exhibit defects in axon-regrowth, target reinnervation, and functional recovery. TFEB/3 deficiency inhibits the expression of injury-responsive repair Schwann cell genes, despite the continued expression of c-Jun, a previously identified regulator of repair Schwann cell function. TFEB/3 binding motifs are enriched in the enhancer regions of injury-responsive genes, suggesting their role in repair gene activation. Autophagy-dependent myelin breakdown is not impaired despite TFEB/3 deficiency. These findings underscore a unique role of TFEB/3 in adult Schwann cells that is required for proper peripheral nerve regeneration.Significance Statement Peripheral nerves have been recognized for their efficient regenerative capabilities compared to the central nervous system neurons. This is due to the remarkable ability of Schwann cells to undergo a reprogramming process, transforming into progenitor-like repair Schwann cells that actively contribute to axon regeneration and overall nerve repair. However, the specific transcriptional regulators responsible for initiating this transformation in the adult peripheral nerve have remained elusive. Our study elucidates a previously undescribed, injury-responsive function of TFEB/3 in adult Schwann cells, showcasing its ability to promote tissue repair. Our findings hold important implications for enhancing nerve regeneration by bolstering the regenerative capacity of glial cells, thereby contributing to advancements in the field of neural tissue repair.
RESUMEN
For several decades, dermatologists have utilized azathioprine to treat numerous debilitating skin diseases. This synthetic purine analog is derived from 6-mercaptopurine. It is thought to act by disrupting nucleic acid synthesis and has recently been found to interfere with T-cell activation. The most recognized uses of azathioprine in dermatology are for immunobullous diseases, generalized eczematous disorders, and photodermatoses. In this comprehensive review, the authors present recent advancements in the understanding of azathioprine and address aspects not covered in prior reviews. They (1) summarize the history of azathioprine; (2) discuss metabolism, integrating information from recent publications; (3) review the mechanism of action with attention paid to the activities of azathioprine not mediated by its 6-mercaptopurine metabolites and review new data about inhibition by azathioprine of the CD28 signal transduction pathway; (4) thoroughly examine thiopurine s-methyltransferase genetics, its clinical relevance, and interethnic variations; (5) review prior uses of azathioprine in the field of dermatology and grade the level of evidence; (6) discuss the use of azathioprine in pregnancy and pediatrics; review (7) key drug interactions and (8) adverse effects; (9) suggest a dosing and monitoring approach different from prior recommendations; and (10) explore the future of azathioprine, focusing on laboratory considerations and therapeutic application.
