Systemic Inflammation Impairs Human Myelopoiesis [scRNA-Seq]

Systemic inflammation (SI) is a prevalent condition with a high mortality rate1. Survivors of hyperinflammatory state of SI frequently enter a long-lasting immunosuppressive state2 deteriorating their life quality3,4. Due to the extensive heterogeneity in SI etiology, the underlying mechanisms are not well understood. Here, we characterized the short and long-term effects of lipopolysaccharide (LPS)-induced SI (LPS-SI, also called endotoxemia5) on blood monocytes and bone marrow (BM) cells. Similar to clinical features of SI, we observed a profound but transient acute LPS response, followed by a long-term immunosuppressed state. Single-cell transcriptomic analysis of LPS-SI acute phase unveiled the loss of BM monocytes and the appearance of an inflammatory monocyte-like (i-Mono’s) population, expressing gene programs similar to a cell state identified in early-stage sepsis patients6. We observed impairment of myelopoiesis one week after LPS-SI manifested by a significant loss of intermediate and non-classical monocytes which is associated with reduced expression of interferon type I (IFN-I) genes. We confirm that this compromised myelopoiesis also happens in late-stage sepsis patients. Importantly, IFNb treatment reverted the LPS-induced immunosuppression in monocytes. Our results deepened the knowledge about SI and its long-lasting effects on myelopoiesis, substantiating the importance of IFN-I in the pathophysiology of SI-induced immunosuppression. Characterization of short and long-term effect of LPS induced systemic inflammation on human hematopoiesis, with especiall focus on myelopoiesis, using bulk and single-cell RNA-seq NOTE FROM SUBMITTER: Not Allowed to Deposit Raw File Due to Donor Consent