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1.
Diabetes ; 73(7): 1112-1121, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38656918

ABSTRACT

Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the interindividual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI ≥25 kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECARs) to estimate glycolysis and oxygen consumption rates (OCRs) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among study participants, they were strongly associated with each other. The ECAR-to-OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin levels, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, whereas monocytes from more insulin-sensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR-to-OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.


Subject(s)
Insulin Resistance , Monocytes , Obesity , Humans , Insulin Resistance/physiology , Insulin Resistance/immunology , Obesity/metabolism , Obesity/immunology , Monocytes/metabolism , Monocytes/immunology , Female , Male , Adult , Middle Aged , Glycolysis , Chemokine CXCL11/metabolism , Chemokine CXCL11/blood , Cytokines/metabolism , Cytokines/blood , Oxygen Consumption
2.
Commun Biol ; 7(1): 430, 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38594506

ABSTRACT

Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.


Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Cancer-Associated Fibroblasts/metabolism , N-Acetylneuraminic Acid/metabolism , Sialic Acid Binding Immunoglobulin-like Lectins/metabolism , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/metabolism , Macrophages/metabolism , Polysaccharides/metabolism , Tumor Microenvironment
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