Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury

Zheng, Xiaojing; Mi, Tiantian; Wang, Rong; Zhang, Zihan; Li, Wenyan; Zhao, Junli; Yang, Peiyan; Xia, Haibin; Mao, Qinwen

doi:10.1002/glia.24175

Cited by 10 publications

(7 citation statements)

References 86 publications

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“…The densities of IBA-1-positive microglia were similar between 4-month-old Fam76b -/- and WT mice ( Figure 7b ). A controlled cortical impact (CCI) mouse model ( Zheng et al, 2022 ), as a widely used model for TBI, was then used to examine the effect of FAM76B on microglia-mediated neuroinflammation. The densities of IBA-1-positive microglia were higher in the hippocampus adjacent to the cortical contusion of Fam76b -/- mice than in that of WT mice or sham controls ( Figure 7c and d ).…”

Section: Resultsmentioning

confidence: 99%

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FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

Wang,

Zheng,

Chai

et al. 2023

eLife

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FAM76B has been reported to be a nuclear speckle localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-κB-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1 in vitro. We further showed that FAM76B suppressed inflammation in vivo using a traumatic brain injury (TBI) mouse model. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediated neuroinflammation via influencing the translocation of hnRNPA2B1in vivo during TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-κB-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.

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Section: Resultsmentioning

confidence: 99%

“…Experimental TBI was performed using the CCI model, as described ( Zheng et al, 2022 ). Briefly, mice were anesthetized with 1.5% pentobarbital sodium at a dose of 50 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

Wang,

Zheng,

Chai

et al. 2023

eLife

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“…7b). A CCI mouse model (Zheng et al 2022) was then used to examine the effect of FAM76B on microglia-mediated neuroinflammation. The densities of IBA-1-positive microglia were higher in the hippocampus adjacent to the cortical contusion of Fam76b -/- mice than in that of WT mice or sham controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

Wang

Zheng

Chai

et al. 2022

Preprint

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FAM76B has been reported to be a nuclear speckle localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-κB-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1in vitro. We further showed that FAM76B suppressed inflammation by regulating the NF-κB pathwayin vivousing a traumatic brain injury (TBI) model in FAM76B knockout mice. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediates neuroinflammation by influencing the translocation of hnRNPA2B1in vivoduring TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-κB-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.

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“…Importantly, advanced studies have proposed that neuroinflammation occurring in the NAc is implicated in the progression of depression [14,68], and our published studies further indicated that NAc neuroinflammation after immune challenge was sufficient to induce depressive-like behaviors in mice [16,46]. Here, we attempted to identify the roles and functions of PGRN in the NAc neuroinflammation-linked depressive-like phenotype, mainly because some in vitro and in vivo studies showed that PGRN plays protective and anti-inflammatory roles in response to brain injury [56,69,70], and the gene expression of PGRN in the NAc observed in our present study was upregulated in LPSinduced NAc neuroinflammation. Unexpectedly, the neuroinflammation-induced depressive-like phenotype in the NAc was attenuated in PGRNKO mice, whereas selectively restoring recombinant PGRN in the NAc of PGRNKO mice predisposed PGRNKO mice to produce depressive-like behaviors under conditions of neuroinflammation in the NAc, indicating that PGRN present in the NAc contributes to depressive-like behaviors under conditions of NAc neuroinflammatory stimulation.…”

Section: Discussionmentioning

confidence: 99%

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

Wang

Lai

Zhou

et al. 2022

J Neuroinflammation

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Background Neuroinflammation in the nucleus accumbens (NAc) is well known to influence the progression of depression. However, the molecular mechanisms triggering NAc neuroinflammation in depression have not been fully elucidated. Progranulin (PGRN) is a multifunctional growth factor that is linked to the innate immune response and inflammation, and PGRN plays a key role in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, the purpose of this study was to validate whether PGRN was involved in the NAc neuroinflammation-promoted depressive-like phenotype. Methods A NAc neuroinflammation-relevant depression-like model was established using wild-type (WT) and PGRN-knockout (KO) mice after NAc injection with lipopolysaccharide (LPS), and various behavioral tests related to cognition, social recognition, depression and anxiety were performed with WT and PGRNKO mice with or without NAc immune challenge. RT‒PCR, ELISA, western blotting and immunofluorescence staining were used to determine the expression and function of PGRN in the neuroinflammatory reaction in the NAc after LPS challenge. The morphology of neurons in the NAc from WT and PGRNKO mice under conditions of NAc neuroinflammation was analyzed using Golgi–Cox staining, followed by Sholl analyses. The potential signaling pathways involved in NAc neuroinflammation in PGRNKO mice were investigated by western blotting. Results Under normal conditions, PGRN deficiency induced FTD-like behaviors in mice and astrocyte activation in the NAc, promoted the release of the inflammatory cytokines interleukin (IL)-6 and IL-10 and increased dendritic complexity and synaptic protein BDNF levels in the NAc. However, NAc neuroinflammation enhanced PGRN expression, which was located in astrocytes and microglia within the NAc, and PGRN deficiency in mice alleviated NAc neuroinflammation-elicited depression-like behaviors, seemingly inhibiting astrocyte- and microglia-related inflammatory reactions and neuroplasticity complexity in the NAc via the p38 and nuclear factor of kappa (NF-κB) signaling pathways present in the NAc after neuroinflammation. Conclusions Our results suggest that PGRN exerts distinct function on different behaviors, showing protective roles in the FTD-like behavior and detrimental effects on the neuroinflammation-related depression-like behavior, resulting from mediating astrocyte and microglial functions from the NAc in different status.

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Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury

Cited by 10 publications

References 86 publications

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors

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