Development of Exhausted Memory Monocytes and Underlying Mechanisms

• Published in: Frontiers in immunology 2021-10, Vol.12, p.778830-778830
• Main Authors: Pradhan, Kisha, Yi, Ziyue, Geng, Shuo, Li, Liwu
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - genetics; ADP-ribosyl Cyclase 1 - metabolism; Animals; Antigens, Ly - genetics; Antigens, Ly - metabolism; B7-2 Antigen - genetics; B7-2 Antigen - metabolism; CD38; Cells, Cultured; exhaustion; Immunologic Memory - drug effects; Immunology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Kruppel-Like Factor 4 - metabolism; Lipopolysaccharides - pharmacology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; monocyte memory; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; pathogenic inflammation; Phenotype; Receptors, Interleukin - genetics; Receptors, Interleukin - metabolism; Sepsis - genetics; Sepsis - immunology; Sepsis - metabolism; Signal Transduction; STAT1 Transcription Factor - metabolism; Toll-Like Receptor 4 - metabolism; TRAM
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.778830

Pathogenic inflammation and immuno-suppression are cardinal features of exhausted monocytes increasingly recognized in septic patients and murine models of sepsis. However, underlying mechanisms responsible for the generation of exhausted monocytes have not been addressed. In this report, we examined the generation of exhausted primary murine monocytes through prolonged and repetitive challenges with high dose bacterial endotoxin lipopolysaccharide (LPS). We demonstrated that repetitive LPS challenges skew monocytes into the classically exhausted Ly6C population, and deplete the homeostatic non-classical Ly6C population, reminiscent of monocyte exhaustion in septic patients. scRNAseq analyses confirmed the expansion of Ly6C monocyte cluster, with elevation of pathogenic inflammatory genes previously observed in human septic patients. Furthermore, we identified CD38 as an inflammatory mediator of exhausted monocytes, associated with a drastic depletion of cellular NAD ; elevation of ROS; and compromise of mitochondria respiration, representative of septic monocytes. Mechanistically, we revealed that STAT1 is robustly elevated and sustained in LPS-exhausted monocytes, dependent upon the TRAM adaptor of the TLR4 pathway. TRAM deficient monocytes are largely resistant to LPS-mediated exhaustion, and retain the non-classical homeostatic features. Together, our current study addresses an important yet less-examined area of monocyte exhaustion, by providing phenotypic and mechanistic insights regarding the generation of exhausted monocytes.