Comparative analyses of monocyte memory dynamics from mice to humans

Abstract

Background Innate monocytes can adopt dynamic “memory” states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking. Methods We performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases. Results Our systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases. Conclusions Key features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.

Alleviation of monocyte exhaustion by BCG derivative mycolic acid

“…Our data demonstrate the potency of methoxy-MA in effectively attenuating monocyte exhaustion generated by prolonged LPS challenge. We validate that exhausted monocytes due to repetitive and prolonged LPS treatment exhibit not only key molecular signatures reported in sepsis (e.g., elevated CD38, PD-L1, and reduced CD86), 74 but also functional signatures of exhaustion (e.g., compromised mitochondria function, potent suppression of T cell proliferation and activation). Our data further demonstrate that M-MA co-treatment may alleviate the development of monocyte exhaustion, at molecular and functional levels.…”