Macrophage regulation of inflammation in type 2 diabetes 2265746

Abstract Introduction Type 2 diabetes is a metabolic disease characterized by chronic, low-grade inflammation that leads to comorbidities that significantly impact quality of life, such as susceptibility to infections and non-healing wounds. Studies in mouse models suggest that macrophages from diabetic contexts exhibit hyper-inflammatory states, but the mechanisms behind this phenomenon are poorly explored and have not yet been investigated in human macrophages. We hypothesize that diabetic macrophages have impaired response mechanisms and are more sensitive to metabolic flux, limiting their ability to effectively resolve inflammation. Methods To study this, we isolated and cultured bone marrow-derived macrophages from WT and db/db mice and stimulated them with inflammatory and resolving cues. We assessed their functional inflammatory response through phenotypic marker changes and cytokine release, and their sensitivity to metabolic flux by culturing in the presence or absence of extracellular glutamine. Results Both healthy and diabetic mature macrophages displayed similar levels of inflammatory response cytokines, inflammatory gene expression changes, and phenotypic marker expression, which was blunted in the absence of glutamine. Interestingly, we observed differences in the differentiation timeline between the two genotypes, which prompted further investigation in their response to maturation cues. Notably, diabetic macrophages lag behind healthy macrophages in expression of CD45 and F4/80, but eventually acquire a similar level of mature cell surface markers by day 7-8 in culture. In addition, diabetic cells have a higher proportion of Ly6Chi cells earlier in culture, which are generally more poised to be pro-inflammatory. Conclusion Ongoing experiments are assessing the inflammatory response of monocytes from diabetic contexts, both mouse and human. This research begins to explore the cell-mediated inflammatory aberrations in type 2 diabetes and may reveal targetable mechanisms to improve patient outcomes. Funding Source TL1TR001864, R01AR084558 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)