Progranulin Promotes Functional Recovery in Rats with Acute Spinal Cord Injury via Autophagy-Induced Anti-inflammatory Microglial Polarization

Shi, Qiang; Wu, Yinghao; Zhang, Baokun; Wu, Shengting; Wang, Xin; Lin, Fujun; Zhang, Guowang; Lian, Xiaojuan; Xu, Jianguang

doi:10.1007/s12035-022-02836-0

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…Progranulin deficiency has been demonstrated to promote neuroinflammation and apoptosis and exacerbate damage ( 64 ). Moreover, progranulin protects lysosomal function and enhances the autophagic flux of microglia, allowing these cells to acquire an anti-inflammatory phenotype ( 65 ) and modulate the expression of GFAP, thereby decreasing the pro-inflammatory activation of astrocytes ( 66 , 67 ). Indeed, previous studies have demonstrated that microglia respond rapidly to pathological stimuli, influencing then the fate of astrocytes ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 99%

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol

Lentilhas-Graça,

Santos,

Afonso

et al. 2024

Front. Immunol.

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IntroductionThe inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed.MethodsIn this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues.ResultsWe demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation.DiscussionOverall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

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Section: Discussionmentioning

confidence: 99%

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol

Lentilhas-Graça,

Santos,

Afonso

et al. 2024

Front. Immunol.

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“…Our subsequent research will focus on PGRN's binding partners and differentially expressed genes regulated by PGRN in influenza virus infection. PGRN contains seven-and-a-half repeats of granulin (GRN) and exhibits anti-inflammatory activity (Tang et al, 2011;Lu et al, 2021;Shi et al, 2022) and PGRN can be cleaved by neutrophil elastase to release GRN which plays a role as a pro-inflammatory factor (Zhu et al, 2002). During influenza virus infection, neutrophil elastase activity is also increased, leading to the conversion of PGRN to GRN.…”

Section: Discussionmentioning

confidence: 99%

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

Zhang

et al. 2023

Front. Microbiol.

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Progranulin (PGRN) plays an important role in influenza virus infection. To gain insight into the potential molecular mechanisms by which PGRN regulates influenza viral replication, proteomic analyzes of whole mouse lung tissue from wild-type (WT) versus (vs) PGRN knockout (KO) mice were performed to identify proteins regulated by the absence vs. presence of PGRN. Our results revealed that PGRN regulated the differential expression of ALOX15, CD14, CD5L, and FCER1g, etc., and also affected the lysosomal activity in influenza virus infection. Collectively these findings provide a panoramic view of proteomic changes resulting from loss of PGRN and thereby shedding light on the functions of PGRN in influenza virus infection.

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“…Spinal cord injury (SCI), one severe trauma of the central nervous system (CNS), impairs sensory and autonomic control and motility (Dong et al, 2023; Huang et al, 2022; Rong et al, 2019; Wu et al, 2022). Increasing evidence has shown that the microenvironment changes after SCI (Shi et al, 2022). Autophagy, a lysosomal‐dependent degradation process, helps maintain homeostasis in the CNS (Li et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

UBC9‐mediated SUMOylation of Lamin B1 enhances DNA‐damage‐induced nuclear DNA leakage and autophagy after spinal cord injury

Fan,

Lou,

Jin

et al. 2024

Journal Cellular Physiology

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Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen–glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin‐related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2‐D08 (a small‐molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy‐related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2‐D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3‐Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.

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Progranulin Promotes Functional Recovery in Rats with Acute Spinal Cord Injury via Autophagy-Induced Anti-inflammatory Microglial Polarization

Cited by 6 publications

References 35 publications

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol

Tandem mass tag-based quantitative proteomics analysis reveals the new regulatory mechanism of progranulin in influenza virus infection

UBC9‐mediated SUMOylation of Lamin B1 enhances DNA‐damage‐induced nuclear DNA leakage and autophagy after spinal cord injury

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