High glucose induces alternative activation of macrophages via PI3K/Akt signaling pathway

Abstract

Our study indicated that high glucose rather than high osmotic pressure induced M2 phenotype via PI3K/Akt signaling pathway.

Macrophage Rewiring by Nutrient Associated PI3K Dependent Pathways

“…Other reports demonstrate that glucose promotes BMM proliferation and decreases LPS induced MHC-II expression, suggesting glucose levels might impact macrophage polarization (60). In line, high glucose levels have been described to induce the expression of Arg-1 and CD206 in macrophages in a PI3K dependent manner (61). Further, evidence of an importance for glucose in M2 responses is provided by studies demonstrating that PI3K-AKT dependent glucose utilization is critical for IL-4 responses (62, 63).…”

“…As TLR4 dependent signaling is increased in obesity, as outlined earlier, PI3Ks would presumably limit pro-inflammatory responses through various mechanisms including the promotion of M2 responses (13–16). Generation of alternatively activated macrophages would also be favored by prevalent hyperglycemia in obesity in a PI3K-AKT dependent manner (61–63). However, high doses of insulin render macrophages insulin resistant, decreasing PI3K signaling and thus inhibiting insulin stimulated glucose uptake through GLUT-1 (36).…”

High Glucose Environments Interfere with Bone Marrow-Derived Macrophage Inflammatory Mediator Release, the TLR4 Pathway and Glucose Metabolism

“…In contrast, Wang et al . 48 showed that a cell lineage of macrophages, RAW 264.7 cells, presented an M2-like macrophage phenotype when cultured under high glucose conditions 48 . Sun et al .…”

“…Wang et al . 48 demonstrated that high glucose leads to activation of RAW 264.7 cells through the PI3K/AKT signalling pathway, which induces the M2 macrophage phenotype defined by arginase and CD206 expression, both of which are blocked when PI3K is inhibited 48 . Similarly, Nandy et al .…”

Insulin Modulates Inflammatory Cytokine Release in Acute Stages and Augments Expression of Adhesion Molecules and Leukocytes in Lungs on Chronic Stages of Paracoccidioidomycosis

“…The role of macrophages and how they are activated in response to a pathogen are key elements of an appropriate immune response, and the metabolic environment has an important impact on this response. Previous studies showed that lineage (29) and peritoneal macrophages (30) cultured under high glucose conditions tend to present M2-like phenotype characteristics, which would polarize them toward an adaptive rather than an innate immune response, and other studies relate the impaired phagocytic ability in AM of diabetic rats to reduced phosphorylation of ERK, Akt, and PKC-d resulting from deficient bonding of leukotrienes to FcgR signaling pathways (31). In addition, Ayala et al show that high glucose levels appear to modify macrophage behavior, affecting different aspects of diabetic (impaired phagocytic ability, reduced production of reactive hydrogen species, and reduced expressions of TLR-4 on the cell surface) and healthy bone marrow-derived macrophages under the same LPS stimulus, hypothesizing that hyperglycemia leaves a glucose legacy, altering the basal steady state of macrophages (32).…”