Progranulin as a Potential Therapeutic Target in Immune-Mediated Diseases

Lan, Yue-Jiao; Sam, Napoleon Bellua; Cheng, Ming; Pan, Hai‐Feng; Gao, Jian

doi:10.2147/jir.s339254

Cited by 35 publications

(17 citation statements)

References 106 publications

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“…GRN is expressed in macrophages and is the most influential element of this molecular network. It encodes progranulin, which participates in inflammation, wound healing, and lysosomal activity 56 . Increasing progranulin levels increased the proportion of regulatory T cells and reduced inflammation and apoptosis in acute lung injury models 32 .…”

Section: Discussionmentioning

confidence: 99%

“…Ghosh et al recently suggested that lysosomal exocytosis is an important mechanism for coronavirus egress. 53 56 Increasing progranulin levels increased the proportion of regulatory T cells and reduced inflammation and apoptosis in acute lung injury models. 32 Progranulin upregulation repressed fibrotic genes and reduced liver fibrosis in animal chronic liver disease models.…”

Section: Discussionmentioning

confidence: 99%

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Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

Kim,

Lim

et al. 2023

Journal of Medical Virology

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The global COVID‐19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 virus has resulted in a significant number of patients experiencing persistent symptoms, including post‐COVID pulmonary fibrosis (PCPF). This study aimed to identify novel therapeutic targets for PCPF using single‐cell RNA‐sequencing data from lung tissues of COVID‐19 patients, idiopathic pulmonary fibrosis (IPF) patients, and a rat transforming growth factor beta‐1‐induced fibrosis model treated with antifibrotic drugs. Patients with COVID‐19 had lower alveolar macrophage counts than healthy controls, whereas patients with COVID‐19 and IPF presented with elevated monocyte‐derived macrophage counts. A comparative transcriptome analysis showed that macrophages play a crucial role in IPF and COVID‐19 development and progression, and fibrosis‐ and inflammation‐associated genes were upregulated in both conditions. Functional enrichment analysis revealed the upregulation of inflammation and proteolysis and the downregulation of ribosome biogenesis. Cholesterol efflux and glycolysis were augmented in both macrophage types. The study suggests that antifibrotic drugs may reverse critical lung fibrosis mediators in COVID‐19. The results help clarify the molecular mechanisms underlying pulmonary fibrosis in patients with severe COVID‐19 and IPF and highlight the potential efficacy of antifibrotic drugs in COVID‐19 therapy. Collectively, all these findings may have significant implications for the development of new treatment strategies for PCPF.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

Kim,

Lim

et al. 2023

Journal of Medical Virology

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“…Therefore, one complex biological activity involving PGRN in astrocytes and microglia is likely to occur in the condition of the NAc neuroinflammatory response and possibly result in surprising outcomes, but further investigation is needed. Finally, PGRN is a complex protein that may have pro-or antiinflammatory properties depending upon the extent of PGRN-regulated proteolysis and the generation of proinflammatory GRN peptides [76]. In cultures of primary human microglia, LPS-increased PGRN cleavage occurs intracellularly, resulting in PGRN production being suppressed while GRN production is increased and switching the role of PGRN in microglia from neurotrophic to inflammatory under inflammatory conditions [75], which is consistent with our evidence of the actions of PGRN in a mouse model of NAc neuroinflammation.…”

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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“…Article published online: 2023-07-17 [5,6], immune cells [7], macrophages [8] and fibroblastic cell [5,6]. The type of disease and its key role in the inflammatory and non-inflammatory pathways in immune-mediated diseases are the main reasons why progranulin plays an important immunomodulatory role [9,10]. A global genetic screen lead to the identification of tumor necrosis factor receptor (TNFR) as the preferential progranulin (PGRN)-associated receptor; PGRN and TNF-α bind to TNFR1 with comparable affinity, and PGRN acts as an antagonist of the TNF-α/TNFR1 interaction [11].…”

Section: Serum-progranulinspiegel Und Krankheitsaktivität Bei Patient...mentioning

confidence: 99%

Serum Progranulin Levels and Disease Activity in Patients with Axial Spondyloarthritis

Mercan¹,

Oktayoğlu

Mete

et al. 2023

Aktuelle Rheumatologie

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Background Axial spondyloarthritides (ax-SpA) are a group of chronic systemic diseases of unknown aetiology, affecting mostly young men, with common features such as inflammatory low back pain, axial skeletal involvement, sacroiliitis, and association with HLA-B27. Inflammatory cytokines, mainly TNF-α, play a role in its aetiopathogenesis. Progranulin (PGRN) is thought to be an anti-inflammatory molecule that acts through the TNF-α pathway. In our study, we aimed to investigate the relationship between serum PGRN levels and disease activity in patients with AS. Material and Methods Forty-five patients between the ages of 18 and 65 who were classified as having ax-SpA according to ASAS classification criteria were included in our study. Forty-five individuals between the ages of 18 and 65 who did not have pregnancy or lactation status, no acute or chronic infection and no malignancy or rheumatic disease were included as the healthy control group. In addition, BASDAI, BASFI, BASMI, ASDAS-CRP, ESR and CRP levels were recorded in the patient group to determine the laboratory and clinical findings of patients with ax-SpA. Results Mean serum progranulin levels were higher in axial SpA patients compared with the control group (5156.72±1274.34 vs. 4836.50±1422.10), but this result was not statistically significant (p=0.275). Serum progranulin levels were negatively correlated with ESR (p=0.031) but ASDAS-CRP (p=0.407) and BASDAI (p=0.297) values were not correlated with the progranulin levels. Conclusion Although we found a negative correlation between progranulin and ESR, we did not find any association between progranulin and disease activity in patients with axSpA. There is a need for new and larger studies to be conducted with a higher number of participants in this patient group and to measure serum PGRN levels as well as antibodies against PGRN.

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Progranulin as a Potential Therapeutic Target in Immune-Mediated Diseases

Cited by 35 publications

References 106 publications

Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

Integrative single‐cell transcriptome analysis provides new insights into post‐COVID‐19 pulmonary fibrosis and potential therapeutic targets

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

Serum Progranulin Levels and Disease Activity in Patients with Axial Spondyloarthritis

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