Resolvin E1 limits IFNg production by NK cells during SAA 2309893

Abstract

Abstract Introduction Severe aplastic anemia (SAA) is a bone marrow (BM) failure syndrome resulting from hematopoietic stem cell (HSC) loss driven by cytotoxic T cells. Natural killer (NK) cells were shown to suppress cytotoxic CD8+ T cells via NKG2D, therefore limiting HSC cell death. However, NK cells also exhibit cytotoxicity during SAA and may sensitize HSCs to T cell killing via IFNg. These data suggest that NK cells play a dual role in SAA pathogenesis, with the capacity to both limit and contribute to HSC loss. Resolvin E1 (RvE1) is a pro-resolving lipid mediator previously shown to improve outcomes in a murine model of SAA. NK cells express RvE1’s receptor ChemR23 and RvE1 has been shown to upregulate NKG2D on NK cells in allergic inflammation. To explore mechanisms of RvE1-mediated protection in SAA we aimed to determine if RvE1 influenced NK function in the BM. Methods We utilized a murine model of SAA and published single-cell RNA-sequencing datasets generated from healthy controls and SAA patients. Results In murine SAA, NK cells were elevated in the BM and a greater proportion were cytotoxic. ChemR23 expression was increased on BM NK cells in SAA in mice and human patients. ScRNA-seq generated from SAA mice treated with RvE1 showed increased Nkg2d but reduced Ifng mRNA expression in NK cells compared to vehicle controls, correlating with survival and improved outcomes. Conclusion These data suggest that RvE1 regulates NK function, refining our mechanistic understanding of how RvE1 improves SAA outcomes. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)