Diego R Hernandez-Espinosa, Gabriela I Medina-Ruiz, Mia G Scrabis, Amantha Thathiah, Elias Aizenman
{"title":"Proinflammatory microglial activation impairs in vitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor.","authors":"Diego R Hernandez-Espinosa, Gabriela I Medina-Ruiz, Mia G Scrabis, Amantha Thathiah, Elias Aizenman","doi":"10.1111/jnc.16239","DOIUrl":null,"url":null,"abstract":"<p><p>Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":" ","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neurochemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/jnc.16239","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.
期刊介绍:
Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.