Lipid rafts in glial cells: role in neuroinflammation and pain processing

Abstract

Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.

AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration

“…AIBP plays a unique role of targeting cholesterol efflux machinery to TLR4-occupied inflammarafts [ 10 , 11 ]. Evidence from clinical and animal studies indicates that TLR4-dependent signaling is an important factor in the pathogenesis of POAG and that this signaling is associated with activated glial cells and contributes to inflammatory responses in experimental glaucoma [ [43] , [44] , [45] ].…”

“…In addition, accumulating evidence suggests that damage-associated molecular patterns (DAMPs) which are endogenous activators of TLR4 released by damaged cells activate microglia and produce inflammatory cytokines [ 10 , 93 ]. The activated microglia-mediated neuroinflammation is an early event in glaucoma, leading to Müller glia activation, neuronal damage, and RGC loss [ 94 , 95 ].…”

“…More recently, we have shown that AIBP binds Toll-like receptor-4 (TLR4), thus mediating selective regulation of lipid rafts in activated cells. It also inhibits TLR4 dimerization, neuroinflammation, and glial activation in the mouse models of neuropathic pain states [ 10 , 11 ]. These findings demonstrate a mechanism by which AIBP regulates neuroinflammation and suggest a therapeutic potential of AIBP for treating neuropathic pain [ 10 ].…”

Neuroprotective Effect of Maternal Resveratrol Supplementation in a Rat Model of Neonatal Hypoxia-Ischemia

“…To further understand the basis of these effects, we aimed at deciphering the molecular mechanisms involved in resveratrol neuroprotection. It was shown that resveratrol could enter the cell by endocytosis via lipid rafts ( Delmas et al, 2013 ; Neves et al, 2016 ), which are present on the plasma membranes of both neurons ( Tsui-Pierchala et al, 2002 ) and astrocytes ( Miller et al, 2020 ). However, once inside the cell, its mode of action is far from being fully understood.…”

Pain Mechanism in Rheumatoid Arthritis: From Cytokines to Central Sensitization

“…When TLR4 is activated, a large number of cytokines, chemokines, and lipids are secreted. These products act on receptors of spinal dorsal horn neurons, enhance pain signaling, and produce hyperalgesia [ 78 ]. Blocking HMGB1-TLR4 signaling in the spinal cord of collagen antibody-induced arthritis (CAIA) mice can reverse the mechanical hypersensitivity in the inflammatory stage and late stage of the model [ 50 ].…”