Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells

Chronic, low-grade inflammation has a widespread and significant impact on health, especially in Western-society. While inflammation is beneficial for the removal of microbes, low-grade inflammation never resolves and can cause or worsen other diseases. However, the process by which low-grade inflammation occurs is poorly understood. As lipopolysaccharide (LPS) is associated with chronic inflammatory diseases, we exposed murine bone-marrow derived monocytes to chronic LPS-stimulation at Low-dose (100pg/mL) or High-dose (1 µg/mL), as well as a PBS control. The cells were profiled for H3K27ac expression and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient mice with LPS exposure was also analyzed for mechanistic insight. We determined that many of the differences between the Low-dose and High-dose conditions are related to the TRIF-dependent pathway of TLR4 signaling. Furthermore, these changes are also seen in the epigenome, suggesting the epigenome may be what leads to the differential response. These findings further characterize the different means utilized in low-grade conditions, and how it might lead to a damaging, non-resolving state. Moreover, our data provide potential targets for future mechanistic or therapeutic studies. Overall design: H3K27ac was profiled in WT murine bone-marrow derived monocytes (BMDMs) treated with PBS, Low-dose LPS (100 pg/mL), or High-dose LPS (1 µg/mL). RNA-seq was also performed using BMDMs isolated from WT mice (PBS, Low, High), TRAM-KO mice (PBS, Low, High), and IRAK-M-KO mice (PBS, High) treated with different levels of LPS. Two replicates were generated per LPS dosage level and genotype. Please note that the records have been updated with the additional samples (GSM5676885 - GSM5676904) on Nov 5, 2021.