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High Omega-6:Omega-3 PUFA Impairs Macrophages Response to Infection and Inflammation

      An important innate immune response involves macrophages eliciting reactive oxygen species (ROS) to kill invading pathogens in response to infection, which are defective in diabetes.
      Moreover, aberrant inflammatory response by macrophages is also a hallmark of diabetes. The impact of elevated fatty acids (FA) on macrophage function during inflammation/infection in hyperglycemia remains unclear. The effects of oleic (OA), palmitic (PA) or linoleic acid
      (LA) in RAW 264.7, a murine macrophage cell line, were evaluated under hyperglycemia. Hyperglycemia per se elevated baseline reactive oxygen species (ROS) from macrophages. When stimulated, with lipopolysaccharide (LPS) or Salmonella enterica Typhimurium (ST), LA exhibited dampened ROS, despite similar LPS doses or ST growth rate. OA incubation repelled invasion with robust ROS release. Although PA induced some apoptosis, surviving macrophages elicited robust ROS response. Interestingly, co-incubation of LA with omega-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) attenuated the intracellular ST invasion and restored ROS production compared to LA alone. Furthermore, glutathione (GSH), a critical thiol for macrophage ROS production was reduced with either hyperglycemia and/or LA. This loss was reversed with overexpression of GSH-synthesizing enzymes glutamate-cysteine ligase and glutathione synthetase, which increased ROS in macrophages exposed to hyperglycemia with/without LA treatment. Overall, these results provide evidence that excess LA with low DHA+EPA as seen in the current Canadian diet could impair macrophage response to incoming pathogens by modulating thiol levels, thereby augmenting infection rates among Canadians suffering from diabetes.
      Supported by the Bill and Melinda Gates Foundation and the Canadian Diabetes Association.