Effect of High Glucose on Human Alveolar Macrophage Phenotype and Phagocytosis of Mycobacteria

Abstract

Diabetes mellitus (DBM) reduces immunological activity and increases susceptibility to various infections, including tuberculosis. Human alveolar macrophage (hAM) functions are altered in DBM.To mimic hyperglycemic conditions in the lung alveolus, we co-cultured a hAM cell line (Daisy cell line) with human umbilical vein endothelial cells (HUVEC) for 48 hours in the presence of culture media alone, normal glucose (5 mM), and high glucose (22 mM). Using flow cytometry, immunophenotype characterization included cell surface markers CD 11c, CD14, CD16, CD86, CD163, CD169, CD206, CX3CR-1, CSF-1R, and MMP9. Phagocytic function was measure by immunofluorescence microscopy at 24 hours after inoculation of cells with GFP-expressing Mycobacterium smegmatis.Direct exposure of AMs to high glucose and exposure in the co-culture system yields different results for the same phenotypic markers. Matrix metalloproteinase-9 (MMP9) expression was increased under both conditions. CD169 and CX3CR1 expression were decreased when AMs were exposed directly to high glucose but increased under co-culture.Immunofluorescence assay revealed that phagocytosis decreased in AMs directly exposed to an increase of glucose from 2.5 mM to normal glucose (5 mM), yet AMs under co-culture did not show decreased phagocytosis until concentrations were raised to 25 mM. Alteration in the expression of certain receptors may contribute to defective sentinel function of AMs, promoting s susceptibility to tuberculosis in a diabetic host. Variability in cell surface marker expression under direct glucose exposure compared to exposure via co-culture reveals that cell signaling between endothelial cells and AMs may play a crucial role in the phenotypic expression of AMs.

Comparative immunopathogenesis in a murine model of inhalative infection with the mucormycetes Lichtheimia corymbifera and Rhizopus arrhizus

“…One reason for that could be that the pathogenesis of Rhizopus infection, as discussed above, is mainly concentrated on the respiratory tract, whereas Lichtheimia with its smaller spores quickly disseminates. Consequently, the impairment of alveolar macrophages by diabetes and high glucose levels [20,21] would mainly affect the Rhizopus-induced mucormycosis and result in higher fungal load in the bloodstream (see Fig 3B). Our results might reflect the epidemiology of mucormycosis in India, where uncontrolled diabetes represents a major risk factor, and where Rhizopus arrhizus (formerly called Rhizopus oryzae) is the most common inducer of mucormycosis [22].…”

Molecular characterization of pre-extensive drug resistant Mycobacterium tuberculosis in Northeast Brazil

“…We found that diabetes was a comorbidity associated with resistance to anti-TB drugs. Data point out to the impact of diabetes on the immune system, favoring the bacillus survival 27 . Diabetes causes increased susceptibility to TB through several mechanisms, including hyperglycemia and cellular insulinopenia, which have indirect effects on macrophage and lymphocyte function 27,28 .…”

“…Data point out to the impact of diabetes on the immune system, favoring the bacillus survival 27 . Diabetes causes increased susceptibility to TB through several mechanisms, including hyperglycemia and cellular insulinopenia, which have indirect effects on macrophage and lymphocyte function 27,28 . Diabetes is Mutations in the gyrA gene were also found in all the 41 samples, constituting the main mechanism of resistance to FQ, with specific mutations at codons 89, 90, 94 and 95.…”

The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe?

“…It was also noted in diabetic mice-associated with intensified indices of oxidative stress-yet these abnormalities were prevented by long-term treatment with angiotensin 1-7 (37). Furthermore, as with aging, experimental diabetes is associated with altered phenotype expression of AM (38) with decreased bactericidal capabilities (39). Taken together, increased susceptibility to serious COVID-19 infection occurs in clinical scenarios associated with increased AM population.…”