LAM Cell-based therapy of inflammatory metabolic diseases

• Applicant: Dr. Lorenz Adlung
• Subject Area: Gastroenterology ; Bioinformatics and Theoretical Biology ; Immunology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528292361

Why do we need to further the study on adipose tissue? Adipose tissue is not only implicated in a vast array of physiological processes such as energy storage and thermoregulation, but also in the pathophysiology of type 2 diabetes mellitus, neuroinflammation, intestinal inflammation, diseases of liver, kidney, the cardio-vascular system, and cancer. Obeity has also recently been identified as a risk factor for Covid 19 severity. A better understanding of adipose tissue biology will thus help us to combat maladies beyond metabolic disorders. During my postdoctoral research at the Weizmann Institute of Science in Israel, we for the first time characterized an important immune cell population in adipose tissue: Lipid-Associated Macrophage (LAM) Cells, which surround mature adipocytes in crown-like structures, thereby preventing leakage of lipids and potentially pro-inflammatory molecules from bursting adipocytes. LAM Cells were found to be functionally conserved in other organs such as the brain, the liver and the cardiovascular system, as well as between mice and humans. Deciphering LAM Cell biogenesis therefore represents a first step towards their utilization as anti-inflammatory mediators in clinical contexts. LAM Cells could serve as a paradigm protecting from inflammation. A current challenge is to obtain LAM Cells in sufficient quality and quantity for adoptive transfer to ameliorate adipose tissue inflammation and systemic immuno-metabolism in recipient mice. To overcome this limitation, we came up with an optimized strategy to induce and cultivate LAM Cells from bone-marrow derived macrophages (BMDMs) ex vivo. Our preliminary data suggests that cultivation of BMDMs with Interleukin-4 and oleate induces a LAM phenotype with a more than ten-fold increase in yield in terms of LAM Cell numbers. Furthermore, our preliminary data suggests that the genetic ablation of LAM Cells leads to elevated pro-inflammatory markers such as Interleukin-6 within the adipose tissue on mRNA level as well as systemically on protein level in the peripheral blood of those mice. Taken together, our preliminary data supports our hypothesis that LAM Cells can be utilized as anti-inflammatory agents in obesity. The here envisioned LAM Cell-based therapy in mice seems technically feasible. In this project, we aim to adoptively transfer ex-vivo produced LAM Cells into obese mice to evaluate to which extend the transferred cells can ameliorate local adipose tissue inflammation and systemic immune-metabolic properties. In the long term, we would like to further explore the biology of LAM Cells and establish them as anti-inflammatory therapeutic agents in systems immunology.

• DFG Programme: Research Grants