Linking CD36-dependent lipid processing to the alveolar macrophage transcriptional program via GATA2

Abstract Alveolar macrophages (AMs) catabolize lipid-rich pulmonary surfactant to support gas exchange and have steady-state anti-inflammatory functions to limit lung tissue damage in response to minor challenge. While it is well appreciated that the lung microenvironment shapes tissue-specific AM function and that this linked with lipid metabolism, little is known about the persistent signaling events that support these functional and metabolic programs. We recently demonstrated that the absence of CISH, a suppressor of cytokine signaling (SOCS) family member, led to a lipid-laden, foamy AM phenotype and the accumulation of pulmonary surfactant. These changes were associated with increased AM expression of the transcription factor GATA2 and RNA-seq analysis of Cish −/−AMs revealed dysregulated expression of lipid-processing genes and increased expression of genes enriched for GATA2-binding motifs. While GATA TFs have been implicated in anti-inflammatory macrophage function and in dysregulation in of lipid-laden athlerosclerotic plaque macrophages, their function in AMs is largely unknown. Our preliminary data suggest that lipid uptake through the scavenger receptor CD36 enhances GATA2 activity and limits AM pro-inflammatory function. We are currently investigating mechanisms by which pulmonary surfactant lipids regulate GATA2 and AM programming, using mice with myeloid specific deletion of CD36; our data suggest that AMs from these mice are impaired in their ability to uptake DPPC, the primary lipid species in surfactant. Defining signaling processes that link CD36 with GATA2 and AM transcriptional and metabolic programs will provide insight into lung homeostasis and support our ability to manipulate AMs therapeutically. R01 HL162658