PLX097681

GSE145242: Erythrophagocytosis drives anti-inflammatory programming of liver macrophages (Bulk RNA seq SPTA CD40 mac)

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Under conditions of erythrolytic stress, which accompanies many disease states, macrophages play key roles in phagocytosing damaged RBCs and preventing the toxic effects of cell-free hemoglobin and heme to maintain homeostasis. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we show that erythrolytic stress promotes expansion of a specific macrophage population in the liver (which we named erythrophagocytes) expressing high levels of Marco and Hmox1 and low levels of MHC class II related genes with an anti-inflammatory gene expression signature. We confirmed the strong anti-inflammatory function of erythrophagocytes in two models of sterile inflammatory liver disease: anti-CD40 antibody-induced systemic inflammation syndrome with necrotizing hepatitis and diet-induced nonalcoholic fatty liver disease (NAFLD). The unique anti-inflammatory phenotype and function of erythrophagocytes was reproduced in vitro by heme-exposure of mouse macrophages, yielding a transcriptional profile that segregated heme-polarized from classical M1- and M2-polarized cells. The phenotype of anti-inflammatory erythrophagocytes coincided with NFE2L2/NRF2 driven gene expression and was abolished in Nfe2l2/Nrf2-deficient macrophages. Our findings point to a novel pathway that regulates macrophage functions to link RBC homeostasis and heme metabolism with innate immunity. SOURCE: Marc Pfefferle (marc.pfefferle@uzh.ch) - University hospital Zürich (USZ)