Development of Exhausted Memory Monocytes and Underlying Mechanisms

Front Immunol. 2021 Oct 28:12:778830. doi: 10.3389/fimmu.2021.778830. eCollection 2021.


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 Ly6Chi population, and deplete the homeostatic non-classical Ly6Clo population, reminiscent of monocyte exhaustion in septic patients. scRNAseq analyses confirmed the expansion of Ly6Chi 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.

Keywords: CD38; TRAM; exhaustion; monocyte memory; pathogenic inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Cells, Cultured
  • Immunologic Memory* / drug effects
  • 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
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Phenotype
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT1 Transcription Factor / metabolism
  • Sepsis / genetics
  • Sepsis / immunology*
  • Sepsis / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism


  • Antigens, Ly
  • B7-2 Antigen
  • Cd86 protein, mouse
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Lipopolysaccharides
  • Ly-6C antigen, mouse
  • Membrane Glycoproteins
  • Receptors, Interleukin
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Ticam2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • lipopolysaccharide, Escherichia coli O111 B4
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1