Oxidative Stress, Lipid Rafts, and Macrophage Reprogramming

Abstract

Oxidant stress, induced under a variety of conditions, is known to lead to the molecular reprogramming of the tissue-fixed macrophage. This reprogramming is associated with an altered response to subsequent inflammatory stimuli, such as lipopolysaccharide (LPS), leading to enhanced liberation of proinflammatory chemokines and cytokines. Due to this altered response, dysregulated immunity ensues, leading to the development of clinical syndromes such as multiple organ dysfunction syndrome (MODS). Although the mechanisms responsible for this altered macrophage activity by oxidant stress remains complex and poorly elucidated, it appears, based on recent research, that early and direct alterations within lipid rafts are responsible. This early and direct interaction with lipid rafts by oxidants leads to the mobilization of annexin VI from lipid raft constructs, leading to the release of calcium. This increased cytosolic concentration of this secondary messenger, in turn, results in the activation of calcium-dependent kinases, leading to further alterations in lipid raft lipids and eventually lipid raft proteins. Due to these lipid raft compositional changes, preassembly of receptor complexes occur, leading to enhanced proinflammatory activation. Within this review, the complexity of oxidant-induced reprogramming within the tissue fixed macrophage as currently understood is explained.

Polymeric proanthocyanidins from Sicilian pistachio (Pistacia vera L.) nut extract inhibit lipopolysaccharide-induced inflammatory response in RAW 264.7 cells

“…In our cell system, direct interference with LPS seems to be ruled out, since pre-treatment of macrophages with the active compounds was followed by washing of cells before stimulation. Modulation and interplay of surface receptors and adaptor proteins are key events of the macrophage response to LPS [34,54,55]. The recently observed modulation of TLR-4 activation by flavonoids [56], and the interaction of proanthocyanidins with NADPH oxidase [57], may shed some light on the activity of these compounds as signaling molecules.…”

The role of oxidative stress during inflammatory processes

“…They involve, at least partly, alterations in lipid raft annexin VI content, activation of calcium-dependent kinases, and the generation of ceramide. In turn, such modifications may result in modifications of lipid raft density and protein composition, with subsequent stimulation of TLR complex assembly (Cuschieri and Maier, 2007;de la Haba et al, 2013).…”

Superoxide induces Neutrophil Extracellular Trap Formation in a TLR-4 and NOX-Dependent Mechanism

“…Our finding builds upon the previous discovery that oxidants enhance TLR-4 signaling in innate immune cells, specifically macrophages. (50) Oxidants accomplish this by altering lipid raft composition, increasing surface receptor density, and affecting transcriptional and translational regulation of proinflammatory genes. Another effect of oxidants on these cells is an increase in intracellular calcium.…”