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Transcriptional affects of KLF2 deletion in bone marrow-derived macrophages

ABSTRACT: We report bulk RNA-sequencing of bone marrow-derived macrophages (BMDMs) harvested from myeloid-specific KLF2 knockout (K2KO) and LysMCre control (LysM) mice

ORGANISM(S): Mus musculus

PROVIDER: GSE149119 | GEO | 2020/08/26

REPOSITORIES: GEO

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Project description:Macrophages (MΦs) are heterogeneous and metabolically flexible with metabolism strongly affecting immune activation. A classic response to pro-inflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, while alternative activation is primarily oxidative which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow derived MΦs (BMDM) from Slc2a1M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and Pentose Phosphate Pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1 demonstrating an incomplete metabolic reprogramming. Slc2a1M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically-activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1M-/- BMDMs had reduced pro-inflammatory metabolites, whereas metabolites indicative of alternative activation - such as ornithine and polyamines - were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr-/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1M-/- BMDMs may have contributed to unstable atheroma formation. Together our findings suggest that while lack of GLUT1 blunted glycolysis and PPP, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated yet phagocytic defects hindered MΦ function in chronic diseases. Control mice are noted as WT or Slc2a1 fl/fl and myeloid GLUT1 deficient are KO or Slc2a1M-/- (LysMCre X Slc2a1fl/fl) for myeloid deficiency.