AMPK signaling in dendritic cells: a metabolic sensor controlling the balance between immunity and tolerance

This research concerns the role of metabolic sensor AMPK, which is activated during low energy levels, and known to suppress the activation of some immune cells. I studied how AMPK regulates the function of dendritic cells (DCs), immune cells that are key regulators of the adaptive immune response. Key findings include that drug-induced AMPK activation in DCs results in metabolic rewiring that leads to immunosuppressive DCs. Furthermore, we show that the AMPK signaling axis in DCs is important for protection against obesity-induced inflammation, while AMPK in DCs inhibits the anti-tumor immune response and thereby promoting tumor growth. Therefore, AMPK activation in DCs may be a promising strategy for the generation of therapeutic tolerogenic DCs, while AMPK inhibition may be beneficial for DC-based cancer therapies. Together, these findings contribute to a better understanding of AMPK as regulator of immunity and tolerance in dendritic cells.Bio X Cell; ChipsoftLUMC / Geneeskund

Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity

Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of DCs. Here, we report that hepatic DCs from high-fat diet-fed (HFD-fed) obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c Delta LKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of Th17-polarizing cytokines and accumulation of hepatic IL-17A+ Th cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c Delta LKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11c Delta AMPK alpha 1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/ or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPK alpha 1 salt-inducible kinase signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesityinduced metabolic dysfunctions by limiting hepatic Th17 responses.Host-parasite interactio

A median fin derived from the lateral plate mesoderm and the origin of paired fins

The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the lateral plate mesoderm (LPM), one hypothesis for the evolution of paired fins invokes derivation from unpaired median fins via a pair of lateral fin folds located between pectoral and pelvic fin territories1. Whilst unpaired and paired fins exhibit similar structural and molecular characteristics, no definitive evidence exists for paired lateral fin folds in larvae or adults of any extant or extinct species. As unpaired fin core components are regarded as exclusively derived from paraxial mesoderm, any transition presumes both co-option of a fin developmental programme to the LPM and bilateral duplication2. Here, we identify that the larval zebrafish unpaired pre-anal fin fold (PAFF) is derived from the LPM and thus may represent a developmental intermediate between median and paired fins. We trace the contribution of LPM to the PAFF in both cyclostomes and gnathostomes, supporting the notion that this is an ancient trait of vertebrates. Finally, we observe that the PAFF can be bifurcated by increasing bone morphogenetic protein signalling, generating LPM-derived paired fin folds. Our work provides evidence that lateral fin folds may have existed as embryonic anlage for elaboration to paired fins

Shaping of dendritic cell function by the metabolic micro-environment

Nutrients are required for growth and survival of all cells, but are also crucially involved in cell fate determination of many cell types, including immune cells. There is a growing appreciation that the metabolic micro-environment also plays a major role in shaping the functional properties of dendritic cells (DCs). Under pathological conditions nutrient availability can range from a very restricted supply, such as seen in a tumor micro-environment, to an overabundance of nutrients found in for example obese adipose tissue. In this review we will discuss what is currently known about the metabolic requirements for DC differentiation and immunogenicity and compare that to how function and fate of DCs under pathological conditions can be affected by alterations in environmental levels of carbohydrates, lipids and amino acids as well as by other metabolic cues, including availability of oxygen, redox homeostasis and lactate levels. Many of these insights have been generated usingin vitromodel systems, which have revealed highly diverse effects of different metabolic cues on DC function. However, they also stress the importance of shifting toward more physiologically relevant experimental settings to be able to fully delineate the role of the metabolic surroundings in its full complexity in shaping the functional properties of DCs in health and disease.Host-parasite interactio