Macrophages become activated initiating innate immune responses. Depending on the signals, macrophages obtain an array of activation phenotypes, described by the broad terms of M1 or M2 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. As a result, the Akt pathway converges inflammatory and metabolic signals to regulate macrophage responses modulating their activation phenotype. Akt is a family of three serine-threonine kinases, Akt1, Akt2, and Akt3. 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. 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.

Activated macrophages are described as classically activated or M1 type and alternatively activated or M2 type, depending on their response to proinflammatory stimuli and the expression of genetic markers including iNOS, arginase1, Ym1, and Fizz1. Here we report that Akt kinases differentially contribute to macrophage polarization, with Akt1 ablation giving rise to an M1 and Akt2 ablation resulting in an M2 phenotype. Accordingly, Akt2 ^−/− mice were more resistant to LPS-induced endotoxin shock and to dextran sulfate sodium (DSS)-induced colitis than wild-type mice, whereas Akt1 ^−/− mice were more sensitive. Cell depletion and reconstitution experiments in a DSS-induced colitis model confirmed that the effect was macrophage-dependent. Gene-silencing studies showed that the M2 phenotype of Akt2 ^−/− macrophages was cell autonomous. The microRNA miR-155, whose expression was repressed in naive and in LPS-stimulated Akt2 ^−/− macrophages, and its target C/EBPβ appear to play a key role in this process. C/EBPβ, a hallmark of M2 macrophages that regulates Arg1, was up-regulated upon Akt2 ablation or silencing. Overexpression or silencing of miR-155 confirmed its central role in Akt isoform-dependent M1/M2 polarization of macrophages.

Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to initiate the inflammatory cascade. Such rapid responses require energy to support orchestrated production of pro-inflammatory mediators and activation of phagocytosis. Being a cell type that is present in diverse environments and conditions, macrophages have to adapt to different nutritional resources. Thus, macrophages have developed plasticity and are capable of utilizing energy at both normoxic and hypoxic conditions and in the presence of varying concentrations of glucose or other nutrients. Such adaptation is reflected on changes in signaling pathways that modulate responses, accounting for the different activation phenotypes observed. Macrophage metabolism has been tightly associated with distinct activation phenotypes within the range of M1-like and M2-like types. In the context of diseases, systemic changes also affect macrophage metabolism, as in diabetes and insulin resistance, which results in altered metabolism and distinct activation phenotypes in the adipose tissue or in the periphery. In the context of solid tumors, tumor-associated macrophages adapt in the hypoxic environment, which results in metabolic changes that are reflected on an activation phenotype that supports tumor growth. Coordination of environmental and pathogenic signals determines macrophage metabolism, which in turn shapes the type and magnitude of the response. Therefore, modulating macrophage metabolism provides a potential therapeutic approach for inflammatory diseases and cancer.