Oxidative Stress, Lipid Rafts, and Macrophage Reprogramming

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.