Comprehensive lipidomics of tissue macrophages reveal LTE4–driven eosinophil survival

Tissue-resident peritoneal macrophages (pMФ) programmed by GATA6 are essential players regulating immunity and tissue balance in the peritoneal cavity. How GATA6 regulates global lipid metabolism is currently unknown. Addressing this, in myeloid-restricted Gata6 -deficient (G ata6 -KO ^mye ) mice, significant changes to the pMФ lipidome were found. First, Bodipy staining and anti-Stokes Raman scattering (CARS) microscopy demonstrated significant intracellular lipid accumulation in lipid droplets in G ata6 -KO ^mye . Untargeted and targeted lipidomics revealed this to result from increased levels of multiple sphingolipid (SL) molecular species, including sphingomyelins, ceramides, and glycosphingolipids, along with upregulation of the cysteinyl leukotriene (CysLTs) pathway at both lipidomic and transcriptional levels. Evidencing a functional role for the lipidomic phenotype, G ata6 -KO ^mye showed significant eosinophil accumulation, associated with decreased apoptosis which was exclusively driven by CysLT signalling. In summary, GATA6 is demonstrated as a regulator of sphingolipid accumulation and CysLT generation in pMФ, with secondary impacts on associated leukocytes through regulation of transcellular CysLT signaling.