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 (Cav), membrane/lipid raft proteins, are expressed in inflammatory cells, yet the role of Caveolin isoforms in microglia physiology is debatable. We propose 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 (CV) 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.

Regulation of intracellular signaling and function by caveolin

“…Is caveolin acting as a chaperone to protect cells? It is possible that caveolin interaction with the cytoskeleton (101, 102) and with proteins such as integrins (103) may be critical to trafficking and localization to various subcellular sites. What are the precise roles of caveolins in regulating intracellular function?…”

“…What are the precise roles of caveolins in regulating intracellular function? Does this regulation derive from influences of caveolin on metabolism at various cellular sites (10, 102, 104) to ultimately impact whole cell and organ function? Are unique subcellular, organelle‐specific proteomes associated with caveolins that dictate homeostatic and pathophysiologic responses?…”

Caveolin-1 in the regulation of cell metabolism: a cancer perspective

“…AP-CAV1 treatment also restored respiratory chain subunit proteins (complexes I–V), preserved mitochondrial function and suppressed apoptotic cell death [59]. Consistently, increased CAV1 expression was observed in an in vitro model of active microglia along with increased mitochondrial number, respiration, and glycolysis [60]. Colon cancer cells (HCT116) that overexpress CAV1 also had its abundant localisation in the mitochondria and, in the low expressing cells (HT29), overexpression of CAV1 led to its enrichment in the mitochondria and reduced apoptosis [61].…”

Role of caveolin-3 in lymphocyte activation

“…Cav-3 expression was thought to be restricted to skeletal, cardiac, and some smooth muscle (Tang et al, 1996). However we have recently demonstrated that Cav-3 is necessary in coordinating microglial activation in the brain (Niesman et al, 2013), and that Cav-3 KO mice have an enhanced neuroinflammatory response to traumatic brain injury (Niesman et al, 2014), suggesting a regulatory role for Cav-3 in immunomodulation in non-muscle cell types. Our current results suggest Cav-3 may be involved in lymphocyte differentiation, proliferation and/or apoptosis.…”