Harnessing distinct tissue-resident immune niches via S100A9/TLR4 improves metabolic imbalance

The interplay between immune cells and metabolic pathways in health and disease is only partially understood. Yet, therapeutic strategies to harness immune cells for improving metabolic diseases are lacking. Here, we focused on insulin deficiency (ID), a metabolic disorder affecting millions worldwide and for which better treatment is needed. Our murine data reveal that ID rearranges the hepatic immune landscape whereby T cell presence lowers, while the Kupffer cell (KC) component increases. This is accompanied by a shift in the transcriptional signature and polarization of the latter towards the KC2 phenotype. By generating ID mice re-expressing Toll-Like Receptor 4 (TLR4) only in KCs, we demonstrate that KC TLR4 is required for the hyperketonemia- and hypertriglyceridemia lowering actions of S100A9 in ID. This effect is accompanied by a TLR4-dependent reshaping of the KC proteome and S100A9-mediated improvements in KC transcriptional aberrancies and polarization defects caused by ID. Moreover, we uncovered immune-niche-specific metabolic effects of S100A9 in ID. While TLR4 in KCs underlies the dyslipidemia improving action of S100A9, TLR4 in bone-marrow derived immune cells underpins the hyperglycemia-improving effects of S100A9 in skeletal muscle in ID. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.