Yi, Ziyue2023-07-282023-07-282023-07-27vt_gsexam:38191http://hdl.handle.net/10919/115881Inflammatory diseases often involve complex and dynamic responses of monocytes, crucial cells of the innate immune system. Understanding these responses, particularly to lipopolysaccharide (LPS), a key inflammatory stimulus, is vital yet remains challenging due to their heterogeneity and plasticity. Upon analyzing available single-cell RNA sequencing data sets, we defined key patterns of monocyte inflammatory responses challenged with varying LPS dosages. We found that high-dose LPS induced the generation of exhausted monocytes with elevated expression of genes associated with pathogenic inflammation and immune suppression.. In contrast, super-low-dose LPS led to a state of low-grade inflammation, characterized by enhanced chemotaxis; immune-enhancement; and adhesion.. Pseudo-time analysis revealed a potential bifurcation of monocytes, starting from a proliferative, less-differentiated and premature state into either the exhausted state (under prolonged high dose LPS challenge) or the low-grade inflammatory state (under the prolonged super-low dose LPS treatment). Complementing our analyses with in vitro cultured murine monocytes, we observed similar exhaustion of monocytes collected from septic murine hearts published in an independent study. Furthermore, we analyzed publicly available scRNAseq datasets regarding monocytes from septic and severe COVID human patients and revealed a similar exhaustion phenotype as we documented in murine exhausted monocytes. In contrast, our analyses of newly published scRNAseq data regarding monocytes from chronic autoimmune patients reveal key distinct low-grade inflammation features. With translational potential, we analyzed the scRNAseq datasets of monocytes trained with 4-PBA, a potent anti-inflammatory compound, and observed that 4-PBA can effectively arrest monocytes in an anti-inflammatory state. Together, our comparative analyses reveal a systems landscape of monocyte memory dynamics with distinct dosage and history of LPS challenges, and offer novel insights for potential therapeutic strategies for modulating both acute sepsis and chronic inflammatory diseases. Our studies also provide a foundation for guiding future mechanistic and translational studies regarding monocyte dynamics and their involvements in health and disease pathogenesis.  ETDenIn CopyrightmonocyteimmunologyinflammationscRNADissertation