Abstract
High glucose levels are associated with changes in macrophage polarisation and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sense the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose-induced increase in α-E catenin when hexosamine biosynthesis (HB) pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of HB pathway in this process. Then, we investigated the potential role of α-E catenin in glucose-induced macrophage polarisation. We find that the reduction in α-E catenin level using siRNA attenuates the glucose-induced changes of both IL-1β and IL-12 mRNA levels under LPS-stimulated condition but does not affect TNF-α expression. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophages via HB pathway and also can modulate the glucose-induced gene expression of inflammatory markers such as IL-1β and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.
Highlights
Macrophages are highly sensitive to environmental stimuli
As we have previously found that β-catenin levels increased with glucose stimulation in macrophage cell lines through the hexosamine biosynthesis (HB) pathway [14], we speculated that the same pathway might account for the glucose-induced up-regulation of α-E catenin
Glucosamine is converted into glucosamine-6-phosphate (GlucN-6-P), bypassing the first three steps required for glucose in the HB pathway (Figure 1C)
Summary
Macrophages are highly sensitive to environmental stimuli. To acquire distinct functional phenotype against host cell infection, macrophages can be polarised into either pro-inflammatory cytokine secreting-classically activated (M1) or anti-inflammatory cytokine secreting-alternatively activated (M2) phenotype. A sustained or even short-term exposure to high glucose levels is known to induce M1 macrophage polarisation [1,2] This has the potential to be relevant in disease such where derangements in glucoregulatory mechanisms play an important role. One such disease is COVID-19 as elevated glucose levels favour SARS-CoV2 infection and effects of glucose levels on macrophage function have been shown to play an important role in this [3,4]. Another example is Type 2 diabetes where hyperglycaemia leads to the accumulation of macrophages and other innate immune cells with M1 phenotype [5].
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