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Decidual polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are essential to immune tolerance during pregnancy. A reduction in the number of these cells is associated with unexplained recurrent pregnancy loss (URPL). In our previous study, we reported that PMN-MDSCs are a group of mature neutrophils that are activated by the decidua microenvironment. In the present study, we show that the decidua microenvironment induces substantial lipid accumulation in neutrophils during their differentiation to PMN-MDSCs. Lower levels of lipid accumulation are detected in PMN-MDSCs from URPL patients, and the amount of lipid in the PMN-MDSCs is positively correlated with the proportion of PMN-MDSCs. Next, we demonstrate that decidua-derived IL6 with the presence of arachidonic acid upregulates fatty acid-binding protein 5 (FABP5) via the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Fy -60ABP5 then continuously stimulates intracellular lipid accumulation. Increased intracellular lipid accumulation mediates arachidonic acid metabolism, a pathway that is significantly activated by the induction of the decidua microenvironment, to stimulate the synthesis of prostaglandin E2 (PGE2) and finally induce the differentiation of PMN-MDSCs. To summarize, decidua-derived IL6 facilitates the differentiation of PMN-MDSCs from neutrophils via the pSTAT3/FABP5/PGE2 pathway. Defects in the process may result in impaired differentiation and dysfunction of PMN-MDSCs in URPL. These findings enhance our understanding of the physiological mechanisms of immune tolerance in pregnancy and provide therapeutic options for URPL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhang, Li, Xiong, Bai, Sun, Chen, Zhang, Li and Zhao.)

The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3 + T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Zhang, Lv, Xing, Shi, Li, Chen, Zuo, Tao, Xiao, Liu and He.)

The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity., (Copyright © 2020 Kramer and Abrams.)