We found that the inflammation/infection-induced HSPC necroptosis and BM failure in Casp8−/− mice can be completely prevented by Ripk3 deletion; however, the HSC self-renewal defects of Casp8−/− HSCs is mediated by Ripk1-Tbk1-Ifnβ signaling independent of Ripk3. Here, CASP8 is linked to infection.