Lnc-C/EBPß Modulates Differentiation of MDSCs Through Downregulating IL4i1 With C/EBPß LIP and WDR5.

Myeloid-derived suppressor cells (MDSCs), which play an important role in tumor and inflammatory diseases, are divided into two subsets CD11b+Ly6ChiLy6G- monocytic MDSC (Mo-MDSC) and CD11b+Ly6Clow/negLy6G+ polymorphonuclear MDSC (PMN-MDSC) with different immunosuppressive function. However, it is poorly understood the mechanism(s) to control differentiation of Mo-MDSCs and PMN-MDSCs. Here, we found that lnc-C/EBPß may promote PMN-MDSC but impede differentiation of Mo-MDSCs in vitro and in vivo. We demonstrated that lnc-C/EBPß mediated differentiation of MDSCs was through downregulating multiple transcripts such as IL4il. Lnc-C/EBPß not only bound to C/EBPß isoform LIP to inhibit the activation of C/EBPß but also interacted with WDR5 to interrupt the enrichment of H3K4me3 mark on the promoter region of IL4i1. Data also imply that conserved homo lnc-C/EBPß has a similar function with mouse lnc-C/EBPß. Since MDSC subsets exert different suppressive function, lnc-C/EBPß may be acted as a potential therapeutic target for inflammatory and tumor-associated diseases.

The Pseudogene Olfr29-ps1 Promotes the Suppressive Function and Differentiation of Monocytic MDSCs.

Long noncoding RNA (lncRNA) plays a critical role in many biological processes, such as cell differentiation and development. However, few studies about lncRNAs regulating the differentiation and development of myeloid-derived suppressor cells (MDSCs) exist. In this study, we identified a lncRNA pseudogene, Olfr29-ps1, which was expressed in MDSCs and upregulated by the proinflammatory cytokine IL6. The Olfr29-ps1 in vertebrates is conserved, and the similarity between the Olfr29-ps1 and human OR1F2P sequence is 43%. This lncRNA promoted the immunosuppressive function and differentiation of monocytic (Mo-)MDSCs in vitro and in vivo It directly sponged miR-214-3p to downregulate miR-214-3p, which may target MyD88 to modulate the differentiation and development of MDSCs. The functions of Olfr29-ps1 were dependent on IL6-mediated N 6-methyladenosine (m6A) modification, which not only enhanced Olfr29-ps1, but also promoted the interaction of Olfr29-ps1 with miR-214-3p Thus, our results demonstrated that the pseudogene Olfr29-ps1 may regulate the differentiation and function of MDSCs through a m6A-modified Olfr29-ps1/miR-214-3p/MyD88 regulatory network, revealing a mechanism for the regulation of myeloid cells and also providing potential targets for antitumor immunotherapy.

Lnc-C/EBPß Negatively Regulates the Suppressive Function of Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSC) are regulators of immune responses in cancer. The differentiation and function of these MDSCs may be regulated through multiple factors, such as microRNAs. However, the effect of long noncoding RNAs (lncRNA) on the differentiation and function of MDSCs is poorly understood. We identified a long noncoding RNA (lncRNA) named lnc-C/EBPß in MDSCs, which may control suppressive functions of MDSCs. Lnc-C/EBPß could be induced in in vitro and in vivo tumor and inflammatory environments. It regulated a set of target transcripts, such as Arg-1, NOS2, NOX2, and COX2, to control immune-suppressive function and differentiation of MDSCs. This lncRNA was also able to bind to the C/EBPß isoform LIP to inhibit the activation of C/EBPß. We also found that the conserved homologue lnc-C/EBPß has a similar function to murine lnc-C/EBPß These findings suggest a negative feedback role for lnc-C/EBPß in controlling the immunosuppressive functions of MDSC in the tumor environment. Cancer Immunol Res; 6(11); 1352-63. ©2018 AACR.

Gut REG3γ-Associated Lactobacillus Induces Anti-inflammatory Macrophages to Maintain Adipose Tissue Homeostasis.

Gut microbiota may not only affect composition of local immune cells but also affect systemic immune cells. However, it is not completely clear how gut microbiota modulate these immune systems. Here, we found that there exist expanded macrophage pools in huREG3γ tgIEC mice. REG3γ-associated Lactobacillus, which is homology to Lactobacillus Taiwanese, could enlarge macrophage pools not only in the small intestinal lamina propria but also in the spleen and adipose tissues. STAT3-mediated signal(s) was a critical factor in the Lactobacillus-mediated anti-inflammatory macrophages. We also offered evidence for critical cellular links among REG3γ-associated Lactobacillus, tissue macrophages, and obesity diseases. Anti-inflammatory macrophages in the lamina propria, which are induced by REG3γ-associated Lactobacillus, may migrate into adipose tissues and are involved in resistance against high-fat diet-mediated obesity. Thus, REG3γ-associated Lactobacillus-induced anti-inflammatory macrophages in gut tissues may play a role in adipose tissue homeostasis.

LncRNA RNCR3 promotes Chop expression by sponging miR-185-5p during MDSC differentiation.

Myeloid-derived suppressor cells (MDSCs) play a critical role in regulating immune responses in cancer and other pathological conditions. Mechanism(s) regulating MDSC differentiation and function is not completely clear, especially epigenetic regulation. In this study, we found that MDSCs express retinal non-coding RNA3 (RNCR3), and the expression in MDSCs is upregulated by inflammatory and tumor associated factors. RNCR3 may function as a competing endogenous RNA (ceRNA) to promote Chop expression by sponging miR-185-5p during MDSC differentiation. RNCR3 knockdown suppressed differentiation and function of MDSCs in vitro and in vivo. Quantitative RT-PCR showed that RNCR3 was negatively regulated by miR-185-5p in MDSCs. MiR-185-5p affected the expansion of MDSCs and reversed the effect of RNCR3 on MDSC differentiation and function through directly targeting Chop. Thus, our results suggest a RNCR3/miR-185-5p/Chop autologously strengthening network to promote MDSC differentiation and suppressive function in response to extracellular inflammatory and tumor-associated signals.

Comparative Cytogenetics Analysis of Chlamys farreri, Patinopecten yessoensis, and Argopecten irradians with Ct-1 DNA by Fluorescence In Situ Hybridization.

The chromosomes of Chlamys farreri, Patinopecten yessoensis, and Argopecten irradians were studied by FISH using C. farreri C(0)t-1 DNA probes. The results showed that C(0)t-1 DNA signals spread on all chromosomes in the three scallops, whereas signal density and intensity were different strikingly. Clustering brighter signals presented in the centromeric and telomeric regions of most C. farreri chromosomes, and in the centromeric or pericentromeric regions of several P. yessoensis chromosomes. Comparative analysis of the mapping indicated a relatively higher homology in the repetitive DNA sequences of the genome between C. farreri and P. yessoensis than that between C. farreri and A. irradians. In addition, FISH showed that the distribution of C(0)t-1 DNA clustering signals in C. farreri displayed completely similar signal bands between homologous chromosomes. Based on the C(0)t-1 DNA fluorescent bands, a more exact karyotype of C. farreri has been obtained. In this study, the comparative analysis based on C(0)t-1 DNA provides a new insight into the chromosomal reconstructions during the evolution process, and it is helpful for understanding an important source of genomic diversity, species relationships, and genome evolution.