Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells

Abstract

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 myeloid-specific 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.

Tristetraprolin regulates the skeletal phenotype and osteoclastogenic potential through monocytic myeloid‐derived suppressor cells

“…27 The present study showed that the expansion of M-MDSCs significantly and adversely affects the skeletal phenotype under conditions of TTP decline, including aging. 26,27 As an RNA-binding protein, TTP functions as a key negative regulator of inflammation by inhibiting the production of multiple pro-inflammatory cytokines. 34 TTP is a key molecular target in the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase-2 (MK2) stress signaling pathways with a primary role in binding to adenosine-uridine rich elements (AREs) in the 3′ untranslated regions (3′-UTRs) by virtue of the tandem CCCH zinc finger within target mRNA transcripts, thus destabilizing and promoting mRNA degradation of targets such as TNFα, IL-1β, and IL-6.…”

“…Recent studies from our group have shown that altered TTP expression greatly influences bone myeloid stem cell population expansion with concomitant increased M‐MDSCs in peripheral tissues 27 . Because of these observations, we wanted to understand the bone phenotypic changes that may directly or indirectly result from the altered M‐MDSCs expansion and differentiation.…”

“…Myeloid‐specific TTP‐deficient (cTTPKO) mice were generated by crossing loxP ‐flanked Zfp 36 ( Zfp 36 flox/flox , TTP f/f ) mice with a mouse line expressing a Cre recombinase specific for myeloid lineage (LysMcre) cells 12 . Genomic DNA was extracted from tail sections for PCR genotyping, and primers were used as described 27 . All animal experiments were performed in the University at Buffalo's Laboratory Animal Facilities according to an Institutional Animal Care and Use Committee approved protocol with adherence to standards articulated in the Animal Research: Reporting of In Vivo Experiments (ARRIVE).…”

“…To compare myeloid progenitor population changes following TTP deficiency, we processed the previously sequenced data from femurs of control, TTPKO, and cTTPKO mice 27 . After sorting cells through scCATCH, an automated platform for cell type identification, the myeloid compartment was selected and progenitor cell types were labeled as previously described 27 .…”

“…To compare myeloid progenitor population changes following TTP deficiency, we processed the previously sequenced data from femurs of control, TTPKO, and cTTPKO mice 27 . After sorting cells through scCATCH, an automated platform for cell type identification, the myeloid compartment was selected and progenitor cell types were labeled as previously described 27 . Data were subjected to Seurat normalization followed by the potential of heat diffusion for affinity‐based transition embedding (PHATE) dimensionality reduction to cluster cells with similar transcriptomic profiles.…”