Glucose regulates expression of pro-inflammatory genes, IL-1 and IL-12, through a mechanism involving hexosamine biosynthesis pathway-dependent regulation of α-E catenin

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 alpha-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose-induced increase in alpha-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 alpha-E catenin in glucose-induced macrophage polarisation. We find that the reduction in alpha-E catenin level using siRNA attenuates the glucose-induced changes of both IL-1(3 and IL-12 mRNA levels under LPS-stimulated condition but does not affect TNF-alpha expression. Together this indicates that alpha-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-1(3 and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.