Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism

The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.