Toll-like receptor 4 protects against irradiation-induced hematopoietic injury by promoting granulopoiesis and alleviating marrow adipogenesis

Zhengxu Sun; Kunpeng Wu; Qiwang Lin; He Fei; Hua Jiang; Tong Chen; Yan Yuan

doi:10.1016/j.bbrc.2019.10.027

Toll-like receptor 4 protects against irradiation-induced hematopoietic injury by promoting granulopoiesis and alleviating marrow adipogenesis

Biochem Biophys Res Commun. 2019 Dec 3;520(2):420-427. doi: 10.1016/j.bbrc.2019.10.027. Epub 2019 Oct 10.

Authors

Zhengxu Sun¹, Kunpeng Wu¹, Qiwang Lin², He Fei², Hua Jiang², Tong Chen³, Yan Yuan⁴

Affiliations

¹ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
² Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, Shanghai, China.
³ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: chentong@fudan.edu.cn.
⁴ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: yuanyan@fudan.edu.cn.

PMID: 31607480
DOI: 10.1016/j.bbrc.2019.10.027

Abstract

Irradiation induces severe damage in the hematopoietic system, which leads to bone marrow hyperplasia, 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.

Keywords: Adipogenesis; Granulocyte; Irradiation; Toll like receptor 4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipogenesis / radiation effects*
Animals
Benzoxazoles / pharmacology
Bone Marrow / metabolism
Bone Marrow / radiation effects
Cell Differentiation
Cells, Cultured
Granulocytes / pathology
Hematopoiesis / radiation effects
Lipopolysaccharides / pharmacology
Male
Mesenchymal Stem Cells / drug effects
Mesenchymal Stem Cells / radiation effects
Mice, Inbred C57BL
Mice, Mutant Strains
NADPH Oxidases / metabolism
Radiation Injuries, Experimental / metabolism
Radiation Injuries, Experimental / pathology*
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism*
Triazoles / pharmacology
Whole-Body Irradiation / adverse effects*

Substances

3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine
Benzoxazoles
Lipopolysaccharides
Tlr4 protein, mouse
Toll-Like Receptor 4
Triazoles
NADPH Oxidases