![]() The different stages of macrophage activation are broadly described as M1 and M2 polarization, both consisting of an array of states that depend on converging signals from inflammatory stimuli and the cellular environment ( 1). The diminished response following prolonged activation has been described as endotoxin tolerance when the inflammatory stimulus derives from Gram-negative bacterial LPS. At later stages of inflammation, macrophages contribute to the resolution of inflammation, and prohibit prolonged inflammatory responses that may lead to tissue injury. Upon activation, transcriptional and epigenetic changes lead to production of proinflammatory cytokines and chemokines, migration, and elimination of the insult. Activation of macrophages is mediated by signaling cascades downstream of TLR and cytokine receptors. Macrophages respond to pathogens and other noxious stimuli, such as apoptotic or necroptotic cell debris, and initiate inflammatory responses. Herein, we review the current knowledge on the role of the Akt signaling pathway in macrophages, focusing on M1/M2 polarization and highlighting Akt isoform–specific functions. Generation of mice lacking individual Akt, PI3K, or mTOR isoforms and utilization of RNA interference technology have revealed that Akt signaling pathway components have distinct and isoform-specific roles in macrophage biology and inflammatory disease regulation, by controlling inflammatory cytokines, miRNAs, and functions including phagocytosis, autophagy, and cell metabolism. Akt is a family of three serine-threonine kinases, Akt1, Akt2, and Akt3. As a result, the Akt pathway converges inflammatory and metabolic signals to regulate macrophage responses modulating their activation phenotype. The PI3K/Akt/mTOR pathway mediates signals from multiple receptors including insulin receptors, pathogen-associated molecular pattern receptors, cytokine receptors, adipokine receptors, and hormones. Depending on the signals, macrophages obtain an array of activation phenotypes, described by the broad terms of M1 or M2 phenotype. Macrophages become activated initiating innate immune responses.
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