ArticlePloS one2012
Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12).
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 1 of them a synthesis that pooled it.
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Who cites it
72 citing papers in PubMed, 1 synthesis or guideline pooled it, 134 citations in OpenAlex.
- A systematic review and meta-analysis of metalloproteinases in patients with Alzheimer's disease and mild cognitive impairment.Journal of Alzheimer's disease : JAD · 2026Pooled it
- Multi-omics prediction of key proteases regulating scar formation and neural repair after spinal cord injury.Neural regeneration research · 2026Article
- Neuroinflammatory Response to Postnatal Administration of Valproic Acid in Wistar Rats as a Mechanism for the Development of Autism Spectrum Disorders: The Role of Neutrophils.Brain sciences · 2026Article
- Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.Molecular medicine (Cambridge, Mass.) · 2026Article
- TNF-α induces type I IFN signalling to suppress neurogenesis and recruit T cells.Nature communications · 2026Article
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.Cell reports · 2024Article
- Progranulin: A promising biomarker and therapeutic target for fibrotic diseases.Acta pharmaceutica Sinica. B · 2024Review
- Tear Fluid Progranulin as a Noninvasive Biomarker for the Monitoring of Corneal Innervation Changes in Patients With Type 2 Diabetes Mellitus.Translational vision science & technology · 2024Article
- Implications of MMP-12 in the pathophysiology of ischaemic stroke.Stroke and vascular neurology · 2024Review
- Review
- Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.Journal of neuroinflammation · 2023Review
- Targeting Progranulin as an Immuno-Neurology Therapeutic Approach.International journal of molecular sciences · 2023Review
- Regulation of extracellular progranulin in medial prefrontal cortex.Neurobiology of disease · 2023Article
- Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach.Brain sciences · 2023Review
- The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke.Cellular and molecular neurobiology · 2023Review
- A Brief Overview of Neutrophils in Neurological Diseases.Biomolecules · 2023Review
- Progranulin Oncogenic Network in Solid Tumors.Cancers · 2023Review
- Progranulin (PGRN) as a regulator of inflammation and a critical factor in the immunopathogenesis of cardiovascular diseases.Journal of inflammation (London, England) · 2023Review
- Progranulin from different gliocytes in the nucleus accumbens exerts distinct roles in FTD- and neuroinflammation-induced depression-like behaviors.Journal of neuroinflammation · 2022Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe essential role of progranulin (PGRN) as a neurotrophic factor has been demonstrated by the discovery that haploinsufficiency due to GRN gene mutations causes frontotemporal lobar dementia. In addition to neurons, microglia in vivo express PGRN, but little is known about the regulation of PGRN expression by microglia. GOAL: In the current study, we examined the regulation of expression and function of PGRN, its proteolytic enzyme macrophage elastase (MMP-12), as well as the inhibitor of PGRN proteolysis, secretory leukocyte protease inhibitor (SLPI), in human CNS cells.
methodsCultures of primary human microglia and astrocytes were stimulated with the TLR ligands (LPS or poly IC), Th1 cytokines (IL-1/IFNγ), or Th2 cytokines (IL-4, IL-13). Results were analyzed by Q-PCR, immunoblotting or ELISA. The roles of MMP-12 and SLPI in PGRN cleavage were also examined.
resultsUnstimulated microglia produced nanogram levels of PGRN, and PGRN release from microglia was suppressed by the TLR ligands or IL-1/IFNγ, but increased by IL-4 or IL-13. Unexpectedly, while astrocytes stimulated with proinflammatory factors released large amounts of SLPI, none were detected in microglial cultures. We also identified MMP-12 as a PGRN proteolytic enzyme, and SLPI as an inhibitor of MMP-12-induced PGRN proteolysis. Experiments employing PGRN siRNA demonstrated that microglial PGRN was involved in the cytokine and chemokine production following TLR3/4 activation, with its effect on TNFα being the most conspicuous.
conclusionsOur study is the first detailed examination of PGRN in human microglia. Our results establish microglia as a significant source of PGRN, and MMP-12 and SLPI as modulators of PGRN proteolysis. Negative and positive regulation of microglial PGRN release by the proinflammatory/Th1 and the Th2 stimuli, respectively, suggests a fundamentally different aspect of PGRN regulation compared to other known microglial activation products. Microglial PGRN appears to function as an endogenous modulator of innate immune responses.
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