Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.
Javid A1, Zlotnikov N1, Pětrošová H1, Tang TT1, Zhang Y1, Bansal AK1, Ebady R1, Parikh M1, Ahmed M1, Sun C1, Newbigging S2, Kim YR1, Santana Sosa M1, Glogauer M1, Moriarty TJ1.
http://journals.plos.org/plosone/articl ... ne.0158019
snip from full text:Abstract
Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.
snip from Discussion section:Neither hyperglycemia nor B. burgdorferi infection affected B. burgdorferi uptake (Fig 5E and 5F) or E. coli survival (Fig 5A and 5B) following co-incubation with bone marrow neutrophils. By contrast, significantly more E. coli survived following incubation with peritoneal neutrophils from hyperglycemic C57BL/6 and C3H/HeN mice than normoglycemic controls (Fig 5C and 5D). Interestingly, E. coli survival following incubation with peritoneal neutrophils isolated from both normoglycemic and hyperglycemic infected C57BL/6 mice was similar to mock-infected normoglycemic animals, but was significantly lower than in mock-infected STZ-treated animals (Fig 5C). B. burgdorferi uptake was also impaired in hyperglycemic animals (Fig 5G and 5H). Approximately 2-fold more B. burgdorferi survived following co-incubation with peritoneal neutrophils from hyperglycemic C3H mice, as determined by LIVE-DEAD staining (Fig 5I and 5J). These data confirmed previous reports that hyperglycemia impairs the ability of activated neutrophils to kill E. coli , and indicated that hyperglycemia also inhibits the ability of activated neutrophils to phagocytose and kill B. burgdorferi.
Our finding that hyperglycemia affected the bacterial uptake function of neutrophils recruited to tissues but not of bone marrow neutrophils also agrees with previous reports that hyperglycemia primarily affects the function of circulation and tissue neutrophils, likely due to dysregulation of neutrophil transition to the fully activated state required for bactericidal activities [15–18,57]. In addition, across all mouse strains and conditions used in our studies, hyperglycemia resulted in more widespread B. burgdorferi colonization and reduced clearance of B. burgdorferi debris both in typical targets of this bacterium (heart and joint), but also in organs frequently affected by hyperglycemia (brain, lung and liver) [3,47,49]. Finally, we found that chemically-induced hyperglycemia in two different mouse strains and genetically-induced hyperglycemia were all associated with reduced B. burgdorferi clearance. Collectively, these data suggest that impaired B. burgdorferi clearance is associated with hyperglycemia itself, and not with hyperglycemia-independent effects of streptozotocin, the Akita mutation, or mouse strain-specific differences in immune function.