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

Abstract

High glucose levels are associated with changes in macrophage polarization 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 of α-E catenin when hexosamine biosynthesis pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of hexosamine biosynthesis pathway in this process. Then, we investigated the potential role of α-E catenin in glucose induced macrophage polarization. We find that the reduction of 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 hexosamine biosynthesis 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.

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“…al. [ 63 ] The study investigated the potential role of α‐E catenin in the polarization of macrophages in high glucose conditions (25 mM). The study suggested the direct influence of LPS stimulation on glucose‐induced IL‐1β secretion, but no changes in TNF‐α expression.…”

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“…In fact, macrophage polarization is characterized by distinct metabolic profiles indicating that nutrient utilization plays a key role in coordinating proper cellular response. This is underscored by the ability of nutrients like glucose to modulate the inflammatory response of macrophages (10,11,17). Further, diseases characterized by deregulated nutrient signaling, like diabetes and other metabolic disorders, often have an inflammatory component.…”

“…Understanding the regulatory mechanisms of these factors is of great importance as uncontrolled inflammatory cytokine expression can lead to tissue damage and contribute to chronic disease. Previous reports indicated that nutrient availability could impact levels of inflammatory cytokine production (7)(8)(9)(10)(11). To assess the impact that Oga deletion had on the macrophage inflammatory response, we analyzed expression of key pro-inflammatory markers, including cytokines, chemokines, metabolic regulators and transcription factors.…”

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