Abstract
Macrophages may be a crucial aspect of diabetic complications associated with the inflammatory response. In this study, we examined how hyperglycaemia, a common aspect of diabetes, modulates bone marrow-derived macrophages (BMDMs) under an inflammatory stimulus. To perform this study, BMDMs from non-diabetic and diabetic (60 mg/kg alloxan, i.v.) male C57BL/6 mice (CEUA/FCF/USP-488) were cultured under normal (5.5 mM) and high glucose (HG, 25 or 40 mM) conditions and stimulated or not stimulated with lipopolysaccharide (LPS, 100 ng/mL). Compared to the BMDMs from the normoglycaemic mice, the LPS-stimulated BMDMs from the diabetic mice presented reduced TLR4 expression on the cell surface, lower phagocytic capacity, and reduced secretion of NO and lactate but greater oxygen consumption and greater phosphorylation of p46 SAPK/JNK, p42 ERK MAPK, pAKT and pPKC-δ. When the BMDMs from the non-diabetic mice were cultured under high-glucose conditions and stimulated with LPS, TLR4 expression was reduced on the cell surface and NO and H2O2 levels were reduced. In contrast, the diabetic BMDMs cultured under high glucose conditions presented increased levels of lactate and reduced phosphorylation of AKT, PKC-δ and p46 SAPK/JNK but enhanced phosphorylation of the p46 subunit of SAPK/JNK after LPS stimulation. High glucose levels appear to modify macrophage behaviour, affecting different aspects of diabetic and healthy BMDMs under the same LPS stimulus. Thus, hyperglycaemia leaves a glucose legacy, altering the basal steady state of macrophages.
Highlights
Different stimuli affect metabolic pathways in macrophages, providing evidence of a connection between metabolic and inflammatory processes[8]
Diabetes impairs glucose control throughout the entire body, with many cells failing to internalize and metabolize glucose due to the lack of insulin, while other types of cells remain in constant contact with high glucose concentrations, promoting intracellular hyperglycaemia[37]
bone marrow-derived macrophages (BMDMs) are the precursors of macrophages that are recruited to sites of inflammation[38], and these cells are different from tissue-specific macrophages[39]
Summary
Different stimuli affect metabolic pathways in macrophages, providing evidence of a connection between metabolic and inflammatory processes[8]. Adenosine 59-monophosphate-activated protein kinase (AMPK) is an energy sensor that acts as an inflammatory and metabolic regulator in most eukaryotic cells[17]. Glucose consumption generates energy in the form of adenosine triphosphate (ATP)[23], but macrophages can focus on a specific part of the glucose metabolic pathway to respond to some types of stimuli, choosing a pathway to generate the mediators that benefit the specific behaviour needed. Along with this intrinsic regulation, the environment can influence whether macrophages skew glucose metabolism towards glycolysis or oxidative phosphorylation (OXPHOS)[8]. Due to the high susceptibility to infections and elevated risk of developing complications after surgery in diabetic patients, failures in inflammation resolution contribute to the high rates of morbidity and mortality in diabetic subjects[29,30]
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