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Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy., (© 2024. The Author(s).)

Background: Mechanical softening of the glial scar region regulates axonal regeneration to impede neurological recovery in central nervous system (CNS) injury. Microglia, a crucial cellular component of the glial scar, facilitate neuronal survival and neurological recovery after spinal cord injury (SCI). However, the critical mechanical characterization of injured spinal cord that harmonizes neuroprotective function of microglia remains poorly understood., Methods: Spinal cord tissue stiffness was assessed using atomic force microscopy (AFM) in a mouse model of crush injury. Pharmacological depletion of microglia using PLX5622 was used to explore the effect of microglia on mechanical characterization. Conditional knockout of Fascin-1 in microglia (Fascin-1 CKO) alone or in combination with inhibition of myosin activity was performed to delve into relevant mechanisms of microglia regulating mechanical signal. Immunofluorescence staining was performed to evaluate the related protein levels, inflammatory cells, and neuron survival after SCI. The Basso mouse scale score was calculated to assess functional recovery., Results: Spinal cord tissue significantly softens after SCI. Microglia depletion or Fascin-1 knockout in microglia limits tissue softening and alters mechanical characterization, which leads to increased tissue pathology and impaired functional recovery. Mechanistically, Fascin-1 inhibits myosin activation to promote microglial migration and control mechanical characterization after SCI., Conclusions: We reveal that Fascin-1 limits myosin activity to regulate mechanical characterization after SCI, and this mechanical signal should be considered in future approaches for the treatment of CNS diseases., (© 2024. The Author(s).)

Following spinal cord injury (SCI), fibrotic scar inhibits axon regeneration and impairs neurological function recovery. It has been reported that T cell-derived interferon (IFN)-γ plays a pivotal role in promoting fibrotic scarring in neurodegenerative disease. However, the role of IFN-γ in fibrotic scar formation after SCI has not been declared. In this study, a spinal cord crush injury mouse was established. Western blot and immunofluorescence showed that IFN-γ was surrounded by fibroblasts at 3, 7, 14, and 28 days post-injury. Moreover, IFN-γ is mainly secreted by T cells after SCI. Further, in situ injection of IFN-γ into the normal spinal cord resulted in fibrotic scar formation and inflammation response at 7 days post-injection. After SCI, the intraperitoneal injection of fingolimod (FTY720), a sphingosine-1-phosphate receptor 1 (S1PR1) modulator and W146, an S1PR1 antagonist, significantly reduced T cell infiltration, attenuating fibrotic scarring via inhibiting IFN-γ/IFN-γR pathway, while in situ injection of IFN-γ diminished the effect of FTY720 on reducing fibrotic scarring. FTY720 treatment inhibited inflammation, decreased lesion size, and promoted neuroprotection and neurological recovery after SCI. These findings demonstrate that the inhibition of T cell-derived IFN-γ by FTY720 suppressed fibrotic scarring and contributed to neurological recovery after SCI.

Clearance of myelin debris caused by acute demyelination is an essential process for functional restoration following spinal cord injury (SCI). Microvascular endothelial cells, acting as "amateur" phagocytes, have been confirmed to engulf and degrade myelin debris, promoting the inflammatory response, robust angiogenesis, and persistent fibrosis. However, the effect of myelin debris engulfment on the function of endothelial tight junctions (TJs) remains unclear. Here, we demonstrate that myelin debris uptake impairs TJs and gap junctions of endothelial cells in the lesion core of the injured spinal cord and in vitro, resulting in increased permeability and leakage. We further show that myelin debris acts as an inducer to regulate the endothelial-to-mesenchymal transition in a dose-dependent manner and promotes endothelial cell migration through the PI3K/AKT and ERK signaling pathways. Together, our results indicate that myelin debris engulfment impairs TJs and promotes the migration of endothelial cells. Accelerating myelin debris clearance may help maintain blood-spinal cord barrier integrity, thus facilitating restoration of motor and sensory function following SCI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

After spinal cord injury (SCI), a large number of blood-derived macrophages infiltrate the lesion site and phagocytose myelin debris to become foamy macrophages, which leads to chronic inflammation. The drug D-4F, an apolipoprotein A-I peptidomimetic made of D-amino acids, has been reported to promote the lipid metabolism of foamy macrophages in atherosclerosis. However, the role and mechanism of D-4F in SCI are still unclear. In this study, we found that D-4F can promote the removal of myelin debris, reduce the formation of foamy macrophages in the lesion core and promote neuroprotection and recovery of motor function after SCI. These beneficial functions of D-4F may be related to its ability to upregulate the expression of ATP-binding cassette transporter A1 (ABCA1), the main transporter that mediates lipid efflux in foamy macrophages because inhibiting the activity of ABCA1 can reverse the effect of D-4F in vitro . In conclusion, D-4F may be a promising candidate for treating SCI by promoting the clearance of myelin debris by foamy macrophages via the ABCA1 pathway.

Background: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRβ), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRβ pathway can mediate fibrotic scar formation after SCI remains unclear., Methods: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRβ pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRβ pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI., Results: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRβ inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI., Conclusions: Our study demonstrates that activation of PDGFRβ pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI., (© 2022. The Author(s).)

After spinal cord injury (SCI), endogenous angiogenesis occurs in the injury core, unexpectedly accompanied by continuous leakage of the blood-spinal cord barrier (BSCB), which may be caused by destruction of the tight junctions (TJs) between vascular endothelial cells-an important structure of the BSCB. Blood-derived macrophages infiltrate into the spinal cord, aggregate to the injury core and then polarize toward M1/M2 phenotypes after SCI. However, the effect of macrophages with different polarizations on the TJs between vascular endothelial cells remains unclear. Here, we demonstrated that from 7 days postinjury (dpi) to 28 dpi, accompanied by the aggregation of macrophages, the expression of claudin-5 (CLN-5) and zonula occludens-1 (ZO-1) in vascular endothelial cells in the injury core was significantly decreased in comparison to that in normal spinal cord tissue and in the penumbra. Moreover, the leakage of the BSCB was severe in the injury core, as demonstrated by FITC-dextran perfusion. Notably, our study demonstrated that depletion of macrophages facilitated the restoration of TJs between vascular endothelial cells and decreased the leakage of BSCB in the injury core after SCI. Furthermore, we confirmed that the endothelial TJs could be impaired by M1 macrophages through secreting IL-6 in vitro, leading to an increased permeability of endothelial cells, but it was not significantly affected by M0 and M2 macrophages. These results indicated that the TJs between vascular endothelial cells were impaired by M1 macrophages in the injury core, potentially resulting in continuous leakage of the BSCB after SCI. Preventing M1 polarization of macrophages or blocking IL-6 in the injury core may promote restoration of the BSCB, thus accelerating functional recovery after SCI., (Copyright © 2022. Published by Elsevier Inc.)

Following spinal cord injury (SCI), microglia gradually migrate to the edge of the lesion, interweaving around the border of the lesion to form the microglial scar, which performs inflammatory limiting and neuroprotective functions. Recent reports showed that Yes-associated protein (YAP) was expressed in astrocytes and promoted the formation of astrocytic scars, while YAP was not expressed in microglia after SCI. YAP and its paralogue transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, which have a similar functional role as both are negatively regulated by the Hippo signalling pathway. However, the expression and function of TAZ after SCI are unclear. Our research group previously found that Fascin-1 was highly expressed in microglia and promoted migration of microglia after SCI, and that, there was a close regulatory relationship between Fascin-1 and YAP/TAZ. In this study, we demonstrated that TAZ was significantly upregulated and mainly expressed in microglia after SCI, and accumulated in the nuclei of microglia in the spinal cord at 14 days post-SCI. Moreover, TAZ was upregulated and accumulated in the nuclei of anti-inflammatory M2-like (M2-L) polarized or myelin-treated microglia. Additionally, XMU-MP-1 (an inhibitor of the Hippo kinase MST1/2 to active TAZ) promoted the aggregation of microglia around the lesion core, resulting in the formation of microglial scars and the functional recovery of mice after SCI. Our findings also indicated that TAZ promoted microglial migration in vitro. Mechanistically, Fascin-1 interacted with TAZ, which upregulated TAZ expression and induced TAZ nuclear accumulation in microglia to promote microglial migration. These findings revealed that TAZ mediated microglial migration to the edge of the lesion core, promoting the formation of microglial scars and functional recovery after SCI. Moreover, TAZ was downstream of Fascin-1, which positively regulated microglial migration after SCI. [ABSTRACT FROM AUTHOR]

The failure of axonal regeneration after spinal cord injury (SCI) results in permanent loss of sensorimotor function. The persistent presence of scar tissue, mainly fibrotic scar and astrocytic scar, is a critical cause of axonal regeneration failure and is widely accepted as a treatment target for SCI. Astrocytic scar has been widely investigated, while fibrotic scar has received less attention. Here, we review recent advances in fibrotic scar formation and its crosstalk with other main cellular components in the injured core after SCI, as well as its cellular origin, function, and mechanism. This study is expected to provide an important basis and novel insights into fibrotic scar as a treatment target for SCI. [ABSTRACT FROM AUTHOR]