Irradiation induces severe damage in the hematopoietic system, which leads to bone marrow hyper-plasia, pancytopenia, and aggravated tissue formation in bone marrow. Studies have shown that Toll-like receptor 4 (TLR4) has a protective effect against irradiation, but the underlying mechanism remains unclear. In this study, we used a TLR4 knockout (TLR4(-/-)) mouse irradiation model and found that the white blood cell and platelet counts in the peripheral blood of TLR4(-/-) mice recovered slowly after irradiation, with bone marrow hyperplasia and increased mortality. Additionally, we found that the proportion of CD11b(+)Gr1(+) granulocytes in the peripheral blood and bone marrow of TLR4(-/-) mice was lower than that of wild-type mice after irradiation. Further, we found that the expression of NADPH Oxidases (NOXs) in the bone marrow was down-regulated after irradiation of TLR4(-/-) mice, and administration of the NOXs inhibitor VAS2870 reduced the proportion of CD11b(+)Gr1(+) cells in the bone marrow and peripheral blood of wild-type mice after irradiation. Irradiation induced severe marrow adipocytes accumulation in TLR4(-/-) mice, TLR4 ligand lipopolysaccharide promoted proliferation and inhibited adipogenic differentiation of mesenchymal stromal cells. In summary, our data suggest that TLR4 promotes myeloid hyperplasia by up-regulating the expression of NOXs after irradiation, prohibits marrow adipogensis and increases the tolerance of mice to irradiation. (C) 2019 Elsevier Inc. All rights reserved.