Comparative analyses of monocyte memory dynamics from mice to humans

Area of Science:

• Immunology
• Cell Biology
• Systems Biology

Background:

• Innate monocytes exhibit dynamic memory states, including low-grade inflammation and pathogenic exhaustion, influencing chronic inflammatory diseases and severe sepsis.
• While conserved features of exhausted monocytes in human and mouse sepsis are suggested, comprehensive systems analyses are lacking.

Purpose of the Study:

• To perform systems analyses of monocyte exhaustion in human and murine sepsis.
• To compare monocyte states resulting from different challenge strengths and histories.

Main Methods:

• Cross-examination of single-cell RNA sequencing (scRNAseq) data from human sepsis patients, experimental septic mice, and in vitro exhausted monocytes.
• Pseudo-time analyses of in vitro programmed monocytes under varying inflammatory conditions.
• Comparative analyses with scRNAseq data from human patients with chronic low-grade inflammatory diseases.

Main Results:

• Key features of monocyte exhaustion (reduced differentiation, pathogenic inflammation, immune suppression) are conserved in human and murine sepsis and reproducible in vitro.
• Monocytes transition to a less-differentiated, proliferative state under prolonged challenges, observed in experimental models and human sepsis.
• Low-dose endotoxin challenges lead to bifurcation into immune-enhancing or chemotactic/adhesive states, rather than exhaustion, relevant to chronic inflammatory diseases.

Conclusions:

• Identified key features of monocyte memory dynamics conserved between human and murine monocytes.
• Demonstrated that varying signal strengths and prolonged innate challenges can capture these conserved monocyte memory states.