title: HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases.
abstract: In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), chronic activation of microglia contributes to disease progression. Activated microglia produce cytokines, chemokines, and other factors that normally serve to clear infection or damaged tissue either directly or through the recruitment of other immune cells. The molecular program driving this phenotype is classically linked to the transcription factor NF-κB and characterized by the upregulation of proinflammatory factors such as IL-1β, TNF-α, and IL-6. Here, we investigated the role of HuR, an RNA-binding protein that regulates gene expression through posttranscriptional pathways, on the molecular and cellular phenotypes of activated microglia. We performed RNA sequencing of HuR-silenced microglia and found significant attenuation of lipopolysaccharide-induced IL-1β and TNF-α inflammatory pathways and other factors that promote microglial migration and invasion. RNA kinetics and luciferase reporter studies suggested that the attenuation was related to altered promoter activity rather than a change in RNA stability. HuR-silenced microglia showed reduced migration, invasion, and chemotactic properties but maintained viability. MMP-12, a target exquisitely sensitive to HuR knockdown, participates in the migration/invasion phenotype. HuR is abundantly detected in the cytoplasmic compartment of activated microglia from ALS spinal cords consistent with its increased activity. Microglia from ALS-associated mutant SOD1 mice demonstrated higher migration/invasion properties which can be blocked with HuR inhibition. These findings underscore an important role for HuR in sculpting the molecular signature and phenotype of activated microglia, and as a possible therapeutic target in ALS and other neurodegenerative diseases.
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, Alabama.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: Prachi
authors.initials: P
authors.lastname: Matsye
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, Alabama.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, Alabama.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: Ying
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, Alabama.
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Genetics, University of Alabama, Birmingham, Alabama.
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.affiliation: Department of Pediatrics, Division of Pediatric Pulmonary Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Preston E
authors.initials: PE
authors.lastname: Bratcher
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, Alabama.|Department of Genetics, University of Alabama, Birmingham, Alabama.|Department of Pediatrics, Division of Pediatric Pulmonary Medicine, National Jewish Health, Denver, Colorado.|Department of Cell, Developmental and Integrative Biology, University of Alabama, Birmingham, Alabama.
authors.forename: Peter H
authors.identifier: 0000-0001-9391-7464
authors.initials: PH
authors.lastname: King
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000593997:Elavl1 protein, mouse; D012333:RNA, Messenger; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: EAAT; Slc38a3; calyx of Held; system A; system N