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Bone marrow TTP deficeincy significantly increased inflammation while reduced plasma lipid and hepatic steatosis in LDLR knockout mice

ABSTRACT: In order to examine the effects of bone marrow TTP deficiency on inflammation and lipid metabolism and determine the driving force during atherosclerosis, 8 week-old female LDLR−/− mice on C57BL/6J background were lethally irradiated and reconstituted with a wild type (TTP+/+) or TTP knockout (TTP−/−) bone marrow cells and fed a Western diet for 12 weeks. Then mice were sacrificed and tissues were collected for analysis. Liver tissues were collected and gene expression was analysed using a whole genome microarray. Bone marrow TTP−/− recipients displayed a significantly higher systemic and multi-organ inflammation compared to the BM-TTP+/+ recipients. BM-TTP−/− mice displayed a significant reduction of serum lipid levels, attenuated hepatic steatosis, and decreased lipid excretion than the control mice. microarray data showed that BM-TTP deficiency modulate liver genes involved in lipid metabolism and inflammatory response. RT-qPCR was used to confirm the results in several genes from microarray data. BM-TTP deficiency did not further accelerate atherorogenesis process in LDLR−/− mice after a Western diet feeding. TTP promoted VLDL to drive proinflammatory mechanism into proatherogenic mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE126481 | GEO | 2019/08/12

REPOSITORIES: GEO

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Project description:Aging results in enhanced myelopoiesis, which is associated with an increased prevalence of myeloid leukemias and the production of myeloid-derived suppressor cells (MDSCs). Tristetraprolin (TTP) is an RNA binding protein that regulates immune-related cytokines and chemokines by destabilizing target mRNAs. As TTP expression is known to decrease with age in myeloid cells, we used TTP-deficient (TTPKO) mice to model aged mice to study TTP regulation in age-related myelopoiesis. Both TTPKO and myeloidspecific TTPKO (cTTPKO) mice had significant increases in both MDSC subpopulations M-MDSCs (CD11b+Ly6ChiLy6G-) and PMN-MDSCs (CD11b+Ly6CloLy6G+), as well as macrophages (CD11b+F4/80+) in the spleen and mesenteric lymph nodes; however, no quantitative changes in MDSCs were observed in the bone marrow. In contrast, gain-of-function TTP knock-in (TTPKI) mice had no change in MDSCs compared with control mice. Within the bone marrow, total granulocyte-monocyte progenitors (GMPs) and monocyte progenitors (MPs), direct antecedents of M-MDSCs, were significantly increased in both cTTPKO and TTPKO mice, but granulocyte progenitors (GPs) were significantly increased only in TTPKO mice. Transcriptomic analysis of the bone marrow myeloid cell populations revealed that the expression of CC chemokine receptor 2 (CCR2), which plays a key role in monocyte mobilization to inflammatory sites, was dramatically increased in both cTTPKO and TTPKO mice. Concurrently, the concentration of CC chemokine ligand 2 (CCL2), a major ligand of CCR2, was high in the serum of cTTPKO and TTPKO mice, suggesting that TTP impacts the mobilization of M-MDSCs from the bone marrow to inflammatory sites during aging via regulation of the CCR2-CCL2 axis. Collectively, these studies demonstrate a previously unrecognized role for TTP in regulating age-associated myelopoiesis through the expansion of specific myeloid progenitors and M-MDSCs and their recruitment to sites of injury, inflammation, or other pathologic perturbations.

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Bone marrow TTP deficeincy significantly increased inflammation while reduced plasma lipid and hepatic steatosis in LDLR knockout mice

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