Fig. 3: Maintenance of endothelial senescence by impaired immune function and expression of HLA-E.

Immune dysfunction, including reduced NK cell cytotoxicity, impaired macrophage phagocytosis, dysregulated NETosis, and shortcomings in complement function—which, incidentally, are common features of ME/CFS and Long COVID—lead to ineffective clearance of senescent cells, enabling their persistence and expression of the SASP over long periods of time. In turn, the endothelial SASP exerts immunomodulatory effects that induce immune activation and recruitment, tissue infiltration, and leukocyte dysfunction and exhaustion, along with vasoconstriction effects, immunothrombosis, and impaired tissue healing and repair. Furthermore, senescent endothelial cells express HLA-E, which evades NK and CD8+T-cell responses. (Created with the paid version of Biorender.com).