Hyperglycemia impairs tolerance and promotes allergic inflammation in mouse models of asthma

Abstract

Abstract Glucose is a key source of energy in systemic and cellular metabolism and has known pro-inflammatory properties. Metabolic disorders (diabetes, insulin resistance) associate with asthma and other allergic diseases. This study sought to understand the role of hyperglycemia in the allergic response. First, we injected fasted Balbc/J mice intraperitoneally (i.p.) with 2g/kg dextrose to test whether hyperglycemia promotes antigen sensitization. Within one hour of injection, we detected a rapid increase in blood glucose levels followed by an increase in expression of inflammatory markers Il1β, Tslp, and Cxcl9 in peritoneal tissue. Concurrently, MHCII+ cells infiltrated the peritoneum. Control experiments showed that inflammatory responses were not due to hyperosmotic effects. To determine whether glucose promotes allergic response, we sensitized mice to chicken egg ovalbumin (OVA) using either alum (standard adjuvant), dextrose, or a vehicle control. Both alum/OVA and dextrose/OVA treated mice mounted lung allergic inflammation in response to inhaled OVA antigen. Dextrose/OVA mice had OVA-specific IgE production similar to alum/OVA group, demonstrating glucose’s ability to promote sensitization. Total cellular infiltrates, bronchoalveolar lavage (BAL) eosinophils, and lung expression of IL-4, IL-13 and IL-33 in dextrose-sensitized mice were equal to or surpassing allergic inflammatory responses in mice given standard adjuvant. Finally, in a separate mouse tolerance model we demonstrated that hyperglycemia impairs development of tolerogenic response to innocuous OVA antigen. These results demonstrate a potentially critical role for glucose dysregulation in loss of tolerance and promotion of allergy.