title: Caveolin isoform switching as a molecular, structural, and metabolic regulator of microglia.
abstract: Microglia are ramified cells that serve as central nervous system (CNS) guardians, capable of proliferation, migration, and generation of inflammatory cytokines. In non-pathological states, these cells exhibit ramified morphology with processes intermingling with neurons and astrocytes. Under pathological conditions, they acquire a rounded amoeboid morphology and proliferative and migratory capabilities. Such morphological changes require cytoskeleton rearrangements. The molecular control points for polymerization states of microtubules and actin are still under investigation. Caveolins (Cavs), membrane/lipid raft proteins, are expressed in inflammatory cells, yet the role of caveolin isoforms in microglia physiology is debatable. We propose that caveolins provide a necessary control point in the regulation of cytoskeletal dynamics, and thus investigated a role for caveolins in microglia biology. We detected mRNA and protein for both Cav-1 and Cav-3. Cav-1 protein was significantly less and localized to plasmalemma (PM) and cytoplasmic vesicles (CVs) in the microglial inactive state, while the active (amoeboid-shaped) microglia exhibited increased Cav-1 expression. In contrast, Cav-3 was highly expressed in the inactive state and localized with cellular processes and perinuclear regions and was detected in active amoeboid microglia. Pharmacological manipulation of the cytoskeleton in the active or non-active state altered caveolin expression. Additionally, increased Cav-1 expression also increased mitochondrial respiration, suggesting possible regulatory roles in cell metabolism necessary to facilitate the morphological changes. The present findings strongly suggest that regulation of microglial morphology and activity are in part due to caveolin isoforms, providing promising novel therapeutic targets in CNS injury or disease.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: iniesman@ucsd.edu.
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Nathan
authors.initials: N
authors.lastname: Zemke
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Fridolfsson
authors.forename: Kristofer J
authors.initials: KJ
authors.lastname: Haushalter
authors.forename: Karen
authors.initials: K
authors.lastname: Levy
authors.forename: Anna
authors.initials: A
authors.lastname: Grove
authors.forename: Rosalie
authors.initials: R
authors.lastname: Schnoor
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Finley
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C495541:Cav1 protein, mouse; C495548:Cav3 protein, mouse; D051242:Caveolin 1; D051244:Caveolin 3; D020033:Protein Isoforms; D012333:RNA, Messenger
keywords: Caveolin; Cytoskeleton; Microglial activation; Mitochondria; Neuroinflammation