Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis

• Published in: European journal of immunology 2022-10, Vol.52 (10), p.1595-1609
• Main Authors: Panda, Sudhasini, Seelan, Diravya M, Faisal, Shah, Arora, Alisha, Luthra, Kalpana, Palanichamy, Jayanth Kumar, Mohan, Anant, Vikram, Naval K, Gupta, Neeraj Kumar, Ramakrishnan, Lakshmy, Singh, Archana
• Format: Article
• Language: English
• Subjects: BCG Vaccine; CD11b antigen; CD14 antigen; Diabetes; Diabetes Mellitus; Etiology; Flow cytometry; Humans; Hyperglycemia; Hyperglycemia - complications; Hyperglycemia - epidemiology; Immune response; Innate immunity; Macrophages; MARCO protein; Pattern recognition receptors; Phagocytes; phagocytosis; Reactive Oxygen Species; Risk factors; Toll-Like Receptor 2; Tuberculosis; Tuberculosis, Pulmonary - microbiology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202249839

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. Potential mechanism for increased M.Tb. susceptibility in uncontrolled diabetic condition: Alterations in macrophage effector functions in terms of bacterial uptake and killing (shown in red arrows) under chronic high glucose environment might increase the susceptibility to TB infection.