Abstract
ABSTRACTFor more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE. As such, interventions to improve the outcomes from GNB infections should seek to suppress the immune response in diabetic hosts.
Highlights
For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing
Just as we found with A. baumannii, DIO diabetic Toll-like receptor 4 (TLR4) KO mice were more resistant to K. pneumoniae and E. coli infection than DIO diabetic wild-type mice (Fig. 5C)
Notwithstanding these conclusions, which were primarily drawn from in vitro and ex vivo assays of phagocyte function, we report that diabetes causes the host to become hypersusceptible to infections caused by Gram-negative bacteria through immune paralysis, independent of bacterial density/clearance
Summary
For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. Over a century of literature has indicated that defective phagocytes in diabetic hosts are responsible for worse outcomes from bacterial infections, leading to the characterization of diabetes as an immunosuppressive state This immunosuppression has long been ascribed to deficits in neutrophil phagocytosis and microbial killing found ex vivo in cells taken from diabetic hosts [4, 5, 10,11,12,13,14,15,16,17,18,19,20,21,22], yet neutropenia is not a substantial risk factor for worse outcomes from A. baumannii infections [23, 24]. We sought to determine the etiology for increased mortality from infections caused by Gramnegative bacteria and to define the source of excess inflammation in the diabetic host
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