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Severe Hyperglycemia Down Regulates Toll‐Like Receptors on Neutrophils: Implications for Propensity to Infections in Diabetics
Author(s) -
Jialal Ishwarlal,
Polage Christopher,
Devaraj Sridevi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.648.11
Subject(s) - tlr2 , innate immune system , phagocytosis , receptor , tlr4 , respiratory burst , immune system , downregulation and upregulation , diabetes mellitus , toll like receptor , immunology , medicine , endocrinology , microbiology and biotechnology , chemistry , biology , biochemistry , gene
While diabetics are predisposed to increased infections the exact mechanisms are unclear. This increased propensity to infections in diabetics may be due to impaired innate immune responses. Toll like receptors (TLR) are pattern recognition receptors of the innate immune response and TLR 2 and 4 are increased on monocytes in diabetic patients. Neutrophils play an important role during the early host response to infection by a coordinated series of effector functions that include phagocytosis, generation of reactive oxygen species (respiratory burst) and killing. However, there is a paucity of data on TLR expression on neutrophils in diabetes. Thus, we examined TLR 2 and 4 expression on neutrophils under diabetic conditions. Neutrophils were isolated from healthy human volunteers and incubated with different concentrations of glucose (5.5 mM, 15 mM, 30 mM glucose with Mannitol serving as an osmotic control). Hyperglycemia upregulated TLR 2 and TLR 4 expression at 15 mM compared to 5.5 mM, however, at very high glucose conditions, 30mM, there was a significant decrease in both TLR2 and TLR4 expression (60% and 80% decrease respectively, p<0.001 by ANOVA). Phagocytosis of S. aureus was decreased in PMN incubated with 30mM glucose (50% decrease, p<0.05) and killing of S. aureus was impaired in PMN incubated with the bacteria at 30mM glucose concentrations compared to 5.5 mM glucose. These studies point to impaired TLR2 and 4 expression and activity on neutrophils resulting in decreased phagocytosis and killing of bacteria at very high glucose (30mM glucose) concentrations. Future studies will examine mechanistic pathways for this impaired TLR activity in neutrophils in diabetes, which could explain the increased susceptibility to infection in diabetic patients.