Hematopoietic stem cell (HSC) aging correlates with an increasing risk of myeloproliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through tumor necrosis factor-α (TNF-α)→ERK→ETS1→interleukin27Ra (IL27Ra) pathway. TNF-α, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid bias of HSCs and also reverses the inhibitory effect of TNF-α on HSCs. Aged IL27Ra-/- mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged wild-type mice. IL27Ra+ HSCs exhibit impaired reconstitution capacity and myeloid-bias compared with IL27Ra- HSCs and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra+ HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity.
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