Macrophage recruitment to the injured nerve initiates a cascade of events, including myelin debris clearance and nerve trophic factor secretion, which contribute to proper nerve tissue repair. However, the mechanism of macrophage recruitment is still unclear. Here, by comparing wild-type with Mlkl^-/- and Sarm1^-/- mice, two mouse strains with impaired myelin debris clearance after peripheral nerve injury, we identify interleukin-17B (IL-17B) as a key regulator of macrophage recruitment. Schwann-cell-secreted IL-17B acts in an autocrine manner and binds to IL-17 receptor B to promote macrophage recruitment, and global or Schwann-cell-specific IL-17B deletion reduces macrophage infiltration, myelin clearance, and axon regeneration. We also show that the IL-17B signaling pathway is defective in the injured central nerves. These results reveal an important role for Schwann cell autocrine signaling during Wallerian degeneration and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.

Significance: Diabetic neuropathy is a commonly occurring complication of diabetes that affects hundreds of millions of patients worldwide. Patients suffering from diabetic neuropathy experience abnormal sensations and have damage in their peripheral nerve axons as well as myelin, a tightly packed Schwann cell sheath that wraps around axons to provide insulation and increases electrical conductivity along the nerve fibers. The molecular events underlying myelin damage in diabetic neuropathy are largely unknown, and there is no efficacious treatment for the disease. The current study, using a diabetic mouse model and human patient nerve samples, uncovered a molecular mechanism underlying myelin sheath damage in diabetic neuropathy and provides a potential treatment strategy for the disease.

Adrenoleukodystrophy protein (ALDP) is responsible for the transport of very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations have been identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural and biochemical characterization. Here we report the cryo-electron microscopy structure of human ALDP with nominal resolution at 3.4 Å. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette transporters, ALDP has two substrate binding cavities formed by the transmembrane domains. Such structural organization may be suitable for the coordination of VLCFAs. Based on the structure, we performed integrative analysis of the cellular trafficking, protein thermostability, ATP hydrolysis, and the transport activity of representative mutations. These results provide a framework for understanding the working mechanism of ALDP and pathogenic roles of disease-associated mutations.

Peripheral neurons have an intrinsic capacity for repair, albeit still challenging. How the nervous system responds to the cellular stress imposed by nerve injury and adjunct therapies impacts axon regeneration and functional outcomes. Here, we summarize some of the key primarily axonal and neuronal adaptive stress responses and mechanisms that underlie the ability of peripheral neurons to regenerate an axon. This includes activation of the unfolded protein response and endoplasmic reticulum membrane-associated molecules, namely Luman/CREB3, a transmembrane basic leucine zipper transcription factor that regulates the encoding of beneficial adaptive stress responses that drive the ability of an injured sensory neuron to regenerate their axon. We also highlight an emerging novel non-invasive strategy, therapeutic acute intermittent hypoxia, that imposes a level of beneficial adaptive stress that can alter gene programs induced by the injury to enhance regeneration in a manner akin to the more invasive yet highly effective electrical nerve stimulation. The ability to manipulate and significantly elevate the intrinsic adaptive stress/repair responses of injured peripheral neurons holds therapeutic promise, with accumulating evidence supporting its clinical use.

Following injury, the peripheral nervous system (PNS) exhibits remarkable regenerative capacity, whereas the central nervous system (CNS) has limited regenerative potential. This difference is partially attributed to distinct postinjury myelin breakdown. However, the underlying mechanisms driving this disparity remain unclear. By comparing the expression profiles of injured peripheral and central nerves in adult male and female C57BL/6J mice, we identified insulin-like growth factor-binding protein 2 (IGFBP2) as a key regulator that determines the differences in myelin breakdown between the injured PNS and CNS. Schwann cell-derived IGFBP2 in the injured PNS promotes myelin breakdown and facilitates axonal regeneration. Furthermore, through lipidomics, we identify ceramide, a sphingolipid regulated by ceramide synthase 6 in injured nerves, as playing a critical role in IGFBP2-mediated myelin breakdown. Conversely, minimal IGFBP2 expression is observed in the injured CNS, contributing to the limited myelin breakdown and axon regeneration in injured CNS. These findings provide insights into the divergent regenerative potential of the PNS and CNS and unveil IGFBP2 and ceramide as promising targets for promoting CNS regeneration after injury.