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In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular complications of diabetes. Recent studies have shown that ROS formation is exacerbated in diabetic monocytes and macrophages due to a glycolytic metabolic shift. Macrophages are important players in the progression of diabetes and promote inflammation through the release of pro-inflammatory cytokines and proteases. Because ROS is an important mediator for the activation of pro-inflammatory signaling pathways, obesity and hyperglycemia-induced ROS production may favor induction of M1-like pro-inflammatory macrophages during diabetes onset and progression. ROS induces MAPK, STAT1, STAT6 and NFκB signaling, and interferes with macrophage differentiation via epigenetic (re)programming. Therefore, a comprehensive understanding of the impact of ROS on macrophage phenotype and function is needed in order to improve treatment of diabetes and its vascular complications. In the current comprehensive review, we dissect the role of ROS in macrophage polarization, and analyze how ROS production links metabolism and inflammation in diabetes and its complications. Finally, we discuss the contribution of ROS to the crosstalk between macrophages and endothelial cells in diabetic complications.

Background Tumor-associated macrophages (TAMs) are a major component of innate immunity supporting primary tumor growth and metastasis. Chemotherapy is one of the main treatment strategies for solid tumors, while chemoresistance is the major limitation of the chemotherapy for patients with various types of cancer. A number of evidence indicate that TAMs can accumulate in tumors after chemotherapy and contribute to chemoresistance. Methods For the endocytic uptake of EGF we used flow cytometry analysis. Confocal microscopy was used for the analysis of stabilin-1-mediated internalization and endocytic trafficking of EGF in CHO cells and in modeled TAMs differentiated in the presence of conditioned supernatants of breast cancer (MCF-7) and colorectal cancer (Colo206F) cell lines. We performed next-generation sequencing of RNA samples obtained from our modeled TAMs. Validation of sequencing data by real-time PCR was performed for selected genes implicated in the endocytic uptake: DNM3, STX8, DENND1A and EHD1. Results For the first time we demonstrated that stabilin-1 ectopically expressed in CHO cells mediates endocytic uptake of EGF, key growth factor stimulating progression of breast and colorectal cancer. In the model of primary human TAMs, we have demonstrated that cisplatin decreases stabilin-1-mediated internalization and endocytic trafficking of EGF, without affecting gene expression of scavenger receptor stabilin-1. Molecular mechanisms of cisplatin effect on TAMs were uncovered using high throughput RNA sequencing. Gene set enrichment analysis identified that cisplatin contributes to defects in endocyting machinery reducing membrane biogenesis and vesicular transport. Significant suppression of DNM3, STX8, DENND1A and EHD1 genes expression by cisplatin was confirmed by RT-PCR. Conclusions We suggested that suppression of receptor-mediated clearance of tumor-supportive factors, such as EGF, by chemotherapeutic drugs may potentially lead to the tumor progression and/or relapse as a mechanism of macrophage-mediated chemoresistance. This study was supported by grand RSF №19-15-00151. Legal entity responsible for the study National Research Tomsk State University. Funding RSF N19-15-00151. Disclosure All authors have declared no conflicts of interest.