Akt Signaling in Macrophages
As we delve into the intricate landscape of cellular signaling of macrophages, the spotlight falls on the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt) pathway, a molecular cascade with profound implications for macrophage function.
This article will explore PI3K/Akt signaling in macrophages, its effect on macrophage polarization and the corresponding effect on atherosclerosis.
PI3K/Akt Pathway in Macrophages
The PI3K/Akt pathway emerges as a key player in macrophage signaling. PI3K, activated in response to extracellular stimuli, catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). This event triggers the recruitment and activation of Akt, a serine/threonine kinase, at the cell membrane.
Fig. 1 The survival signaling pathways related to the PI3K/Akt pathway in mouse macrophages.1
In the realm of macrophages, this pathway assumes a central role in transducing signals from various immune modulators. Akt, once activated, phosphorylates downstream effectors, modulating processes such as cell survival, proliferation, and metabolism.
Impact of Akt Signaling on Macrophage Polarization
Akt signaling has a decisive role in modulating macrophage polarization. It is well known that PI3K/Akt activation significantly promotes macrophage polarization, which in turn stimulates or suppresses the immune response.
Studies revealed that PI3K/Akt activation promotes M2 polarization by upregulating Arg-1 and Fizz1 and inhibiting the NF-κB pathway.
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Activation of Akt has been associated with the promotion of M2 macrophage polarization, characterized by anti-inflammatory properties and tissue repair functions. Akt achieves this by modulating key transcription factors, such as STAT6 and PPARγ, which orchestrate the expression of M2-associated genes.
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Conversely, inhibition of Akt signaling has been linked to the promotion of M1 macrophage polarization, marked by pro-inflammatory responses and pathogen clearance.
The intricate balance of Akt activity thus plays a pivotal role in shaping the macrophage phenotype, thereby influencing the immune landscape.
Atherosclerosis, a chronic inflammatory disease, progresses with lipid metabolism disorder and macrophage foam cell formation. Akt signaling, of note, actively participates in this pathological process. Macrophage-derived foam cells, loaded with oxidized low-density lipoprotein (ox-LDL) via scavenger receptors, express various adhesion molecules, inflammatory mediators, and matrix-degrading proteases, ultimately leading to atherosclerotic lesion progression.
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Akt modulates macrophage-foam cell formation via PPARγ and PPARδ co-activator expression regulation.
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Akt regulates AMPK activity, thus affecting lipid metabolism, inflammation, foam cell formation, and lesion instability in atherosclerosis.
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Akt-deficient or -inhibited macrophages exhibit impaired phagocytosis and efferocytosis, proliferative/apoptotic balance, and inflammatory responses, emphasizing the therapeutic implications of macrophage-centric Akt modulation
Unraveling the intricate Akt signaling in macrophages and its implications in balancing the physiological and pathological processes can pave the way for devising innovative and precise therapeutic strategies.
Creative Biolabs remains at the forefront of unraveling the intricacies of cellular signaling pathways of macrophages, providing a platform for innovative research and the development of novel therapeutic interventions. The exploration of Akt signaling in macrophages exemplifies the commitment to advancing scientific knowledge and translating discoveries into tangible clinical benefits.
Reference
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Linton, MacRae F.,et al "Akt signaling in macrophage polarization, survival, and atherosclerosis." International journal of molecular sciences 20.11 (2019): 2703.
