Search

Increased glycolysis is a metabolic trait of activated innate immune cells and supports functional changes including cytokine production. Insulin drives glycolysis in nonimmune cells, yet its metabolic effects on human innate immune cells remain unexplored. Potential effects of insulin on immune cell metabolism may occur acutely after a postprandial increase in plasma insulin levels or as a consequence of chronically elevated insulin levels as observed in obese insulin-resistant individuals and patients with diabetes. Here, we investigated the effects of acute and chronic exposure to insulin on metabolism and function of primary human monocytes. Insulin acutely activated the PI3K/Akt/mTOR pathway in monocytes and increased both oxygen consumption and glycolytic rates. Functionally, acute exposure to insulin increased LPS-induced IL-6 secretion and reactive oxygen species production. To model chronically elevated insulin levels in patients with diabetes, we exposed monocytes from healthy individuals for 24 h to insulin. Although we did not find any changes in expression of metabolic genes that are regulated by insulin in non-immune cells, chronic exposure to insulin increased LPS-induced TNFα production and enhanced MCP-1-directed migration. Supporting this observation, we identified a positive correlation between plasma insulin levels and macrophage numbers in adipose tissue of overweight individuals. Altogether, insulin acutely activates metabolism of human monocytes and induces a shift toward a more proinflammatory phenotype, which may contribute to chronic inflammation in patients with diabetes.

Sodium butyrate is well-known for its immune-modulatory properties. Studies until now only focused on the in vitro effects of butyrate or assessed local effects in the gut upon butyrate administration. In this trial, we studied the systemic anti-inflammatory effects induced by sodium butyrate supplementation in humans. Nine healthy (Lean) and ten obese (metabolic syndrome group, MetSyn) males were given 4 grams sodium butyrate daily for 4 weeks. PBMCs were isolated before and after supplementation for direct stimulation experiments and induction of trained immunity by oxidized low-density lipoprotein (oxLDL), β-glucan, or Bacillus Calmette-Guérin vaccine (BCG). Butyrate supplementation moderately affected some of the cytokine responses in the MetSyn group. In the direct stimulation setup, effects of butyrate supplementation were limited. Interestingly, butyrate supplementation decreased oxLDL-induced trained immunity in the MetSyn group for LPS-induced IL-6 responses and Pam3CSK4-induced TNF-α responses. Induction of trained immunity by β-glucan was decreased by butyrate in the MetSyn group for Pam3CSK4-induced IL-10 production. In this study, while having only limited effects on the direct stimulation of cytokine production, butyrate supplementation significantly affected trained immunity in monocytes of obese individuals with metabolic complications. Therefore, oral butyrate supplementation may be beneficial in reducing the overall inflammatory status of circulating monocytes in patients with metabolic syndrome.

Contains fulltext : 197966.pdf (publisher's version ) (Open Access)

Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.