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The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial‐derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol‐25‐hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well‐understood. Using floxed‐reporter Ch25h knock‐in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h‐deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h‐deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations. Synopsis: Cholesterol 25‐hydroxylase (Ch25h) expression increases in central nervous system‐endothelial cells (ECs) during inflammation and regulates lipid secretion. Partial loss of Ch25h in ECs promotes polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC) expansion and reduces experimental autoimmune encephalomyelitis (EAE) severity. Ch25h expression and related 25‐hydroxycholesterol (25‐OHC) are increased in ECs during neuroinflammation.Ch25h‐specific ablation from the microvascular endothelium alters fatty acid desaturase 2 (FADS2) expression, which promotes the production of anti‐inflammatory lipids, in particular Prostaglandin E2 (PGE2).25‐OHC and PGE2 control PMN‐MDSC expansion.Partial loss of Ch25h promotes PMN‐MDSC accumulation within the central nervous system (CNS) and attenuates EAE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Elimination of the posttraumatic inflammatory response and recovery of homeostasis are crucial for the positive prognosis of trauma patients. Myeloid‐derived suppressor cells (MDSCs) are known to play a regulatory role in the posttraumatic immune response in mice, but their induction source and involved potential mechanism are poorly understood. Here, we report that polymorphonuclear MDSCs (PMN‐MDSCs) are activated after trauma and are closely associated with the progression of the posttraumatic inflammatory response. In humans, lectin‐type oxidized LDL receptor 1 (LOX1) was used to specifically characterize LOX1+ PMN‐MDSCs. Trauma patients showed high intracellular reactive oxygen species (ROS) production, as well as activation of LOX1+ PMN‐MDSCs. These MDSCs contribute to the anti‐inflammatory immune response by regulating the Treg/Th17 and Th2/Th1 balances after trauma, increasing the levels of anti‐inflammatory factors, and decreasing the levels of proinflammatory factors. The number of LOX1+ PMN‐MDSCs was positively correlated with the positive clinical prognosis of trauma patients with infection. Activation of LOX1+ PMN‐MDSCs is mediated by NF‐κB signal, and TGF‐β1 may be as an important inducer for LOX1+ PMN‐MDSCs in the posttraumatic cytokine environment. In a pseudofracture trauma mouse model, we also observed the activation of PMN‐MDSCs, accompanying high levels of intracellular ROS production, NF‐κB phosphorylation, and changes in the inflammatory environment, in particularly by regulating the Treg/Th17 and Th2/Th1 balance. And more significantly, posttraumatic inflammation was alleviated in mice after transferring trauma‐derived PMN‐MDSCs, but aggravated after injecting with Gr1 agonistic antibody. These findings provide evidence for the specific role of PMN‐MDSCs in the regulation of posttraumatic inflammation. [ABSTRACT FROM AUTHOR]

The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells "conditioned" with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immunotherapy. This study underlines the importance of further optimization of both CAR T-cells and clinical trial in order to target elements of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the predictive capability of neutrophil‐to‐apolipoprotein A1 ratio (NAR) for predicting overall survival (OS) among patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE). Patients and Methods: We investigated the clinical features of 554 patients with HCC receiving TACE and assessed NAR's predictive value for OS with 222 patients (the discovery cohort) and 332 patients (the validation cohort). The association of NAR with circulation lectin‐type oxidized low‐density lipoprotein receptor‐1–positive (LOX‐1+) polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) was illustrated. Results: Multivariate Cox regression revealed that lymphocyte count; Tumor, Node, Metastasis (TNM) stage; and NAR were independent prognostic factors in the discovery cohort. The validation cohort confirmed the independent prognostic value of TNM stage and NAR. Patients with low NAR (<2.7) displayed significantly increased OS in the discovery cohort (59.8 months vs. 21 months), the validation group (38.0 months vs. 23.6 months), and the total cohort (44.1 months vs. 22.0 months). A Cox proportional hazards model was used to combine Cancer of the Liver Italian Program (CLIP) score with discretized NAR. C‐index illustrated that NAR‐integrated CLIP score was the best model compared with NAR and CLIP score. Furthermore, NAR‐CLIP presented superior predictive capacity for 10‐, 20‐, 30‐, 40‐, 50‐, and 60‐month survival compared with CLIP score by survival receiver‐operator characteristic analysis in the discovery cohort, validation cohort, and total cohort. NAR was significantly associated with LOX‐1+ PMN‐MDSCs by linear regression. Conclusion: This study identified NAR as an independent predictor for OS among patients with HCC receiving TACE. NAR reflected circulation LOX‐1+ PMN‐MDSC level. Implications for Practice: The present study identified neutrophil‐to‐apolipoprotein A1 ratio (NAR) as an independent predictor for overall survival among patients with hepatocellular carcinoma receiving transarterial chemoembolization. NAR reflected circulation level of lectin‐type oxidized low‐density lipoprotein receptor‐1–positive polymorphonuclear myeloid‐derived suppressor cells. This article reports on the predictive capability of neutrophil‐to‐apolipoprotein A1 ratio for predicting overall survival among patients with hepatocellular carcinoma receiving transarterial chemoembolization. [ABSTRACT FROM AUTHOR]

Intestinal trefoil factor 3 (TFF3) plays an important role in repairing the intestinal mucosa. However, the detailed mechanism regarding immune regulation by TFF3 is not well defined. Here, we reported that treatment of mouse BM cells and human peripheral blood mononuclear cells from healthy volunteers with TFF3 activated polymorphnuclear myeloid‐derived suppressor cells (PMN‐MDSCs) in vitro. We also found that prostaglandin E2 is a major TFF3‐mediated MDSC target, and that NF‐κB/COX2 signaling was involved in this process. Moreover, TFF3 treatment or transfer of TFF3‐derived PMN‐MDSCs (TFF3‐MDSCs) to experimental necrotizing enterocolitis (NEC) mice caused PMN‐MDSC accumulation in the lamina propria (LP), which was associated with decreased intestinal inflammation, permeability, bacterial loading, and prolonged survival. Interestingly, no NEC severity remission was observed in Rag1 KO mice that were given TFF3‐MDSCs, but coinjection with CD4+ T cells significantly relieved NEC inflammation. Overall, TFF3 mediates the NF‐κB/COX2 pathway to regulate PMN‐MDSC activation and attenuates NEC in a T‐cell‐dependent manner, which suggests a novel mechanism in preventing NEC occurrence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Hyperactivation of the type 2 immune response is the major mechanism of allergic asthma, in which both group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells participate. Myeloid‐derived suppressor cells (MDSCs) alleviate asthma by suppressing Th2 cells. However, the potential effects of MDSCs on the biological functions of ILC2s remain largely unknown. Here, we examined the roles of MDSCs (MDSCs) in the modulation of ILC2 function. Our results showed that polymorphonuclear (PMN)‐MDSCs, but not monocytic (M‐) MDSCs, effectively suppressed the cytokine production of ILC2s both in vitro and in vivo, thereby alleviating airway inflammation. Further analyses showed that cyclo‐oxygenase‐1 may mediate the suppressive effects of PMN‐MDSCs on ILC2 responses. Our findings demonstrated that PMN‐MDSCs may serve as a potent therapeutic target for the treatment of ILC2‐driven allergic asthma. Polymorphonuclear MDSCs could relieve ILC2‐mediated allergic asthma via suppression of ILC2 function, in which cyclooxygenase‐1 may participate. [ABSTRACT FROM AUTHOR]