Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis.

Abstract

Diabetes mellitus (DM) alters immune responses and given the rising prevalence of DM in tuberculosis (TB) endemic countries; hyperglycemia can be a potential risk factor for active TB development. However, the impact of hyperglycemia on TB-specific innate immune response in terms of macrophage functions remains poorly addressed. We assessed macrophage effector functions in uncontrolled DM patients with or without TB infection (PTB+DM and DM), non-diabetic TB patients (PTB), and non-diabetic-uninfected controls. Phagocytic capacity against BCG and surface expression of different pattern recognition receptors (PRRs) (CD11b, CD14, CD206, MARCO, and TLR-2) were measured via flow cytometry. Effector molecules (ROS and NO) required for bacterial killing were assessed via DCFDA and Griess reaction respectively. A systematic dysregulation in phagocytic capacity with concurrent alterations in the expression pattern of key PRRs (CD11b, MARCO, and CD206) was observed in PTB+DM. These altered PRR expressions were associated with decreased phagocytic capacity of macrophages. Similarly, ROS was aberrantly higher while NO was lower in PTB+DM. These altered macrophage functions were positively correlated with increasing disease severity. Our results highlight several key patterns of immune dysregulation against TB infection under hyperglycemic conditions and highlight a negative impact of hyperglycemia with etiology and progression of TB.