CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells.

BACKGROUND

Activated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe sepsis.

METHODS

We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analysed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and humans.

RESULTS

LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signalling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 messenger RNA and NAMPT in renal stromal cells and CD38-positive macrophages, respectively.

CONCLUSION

Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signalling pathways between mice and human sepsis. NAMPT signalling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.