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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.

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy. Although studies have shown that myeloid-derived suppressor cells (MDSCs) play an important role in maintaining feto-maternal tolerance, little is known about the role of MDSCs in pregnancies with intrauterine growth retardation (IUGR). Here, we reported that the activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) during pregnancy was closely associated with fetal growth. In humans, class E scavenger receptor 1 (SR-E1), a distinct marker for human PMN-MDSCs, was used to investigate PMN-MDSC function during pregnancy. Continuous activation of SR-E1(+) PMN-MDSCs was observed in all stages of pregnancy, accompanied by high cellular levels of ROS and arginase-1 activity, mediated through STAT6 signaling. However, SR-E1(+) PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity, lower arginase-1 activity and ROS levels, and decreased STAT6 phosphorylation level, which were accompanied by an increase in inflammatory factors, compared with those in normal pregnancies. Moreover, the population of SR-E1(+) PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR. In mice, decreases in cell population, suppressive activity, target expression levels, and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies, which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice. Interestingly, the growth-promoting factors (GPFs) secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development. These findings collectively support that PMN-MDSCs have another new role in pregnancy, which can improve adverse neonatal outcomes.

Chronic inflammatory bowel disease (IBD) is strongly associated with the development of colitis-associated tumorigenesis (CAT). Despite recent advances in the understanding of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) responses in cancer, the mechanisms of these cells during this process remain largely uncharacterized. Here, we discovered a glycoprotein, olfactomedin-4 (OLFM4), was highly expressed in PMN-MDSCs from colitis to colorectal cancer (CRC), and its expression level and PMN-MDSC population positively correlated with the progression of IBD to CRC. Moreover, mice lacking OLFM4 in myeloid cells showed poor recruitment of PMN-MDSCs, impaired intestinal homeostasis, and delayed development from IBD to CRC, and increased response to anti-PD1 therapy. The main mechanism of OLFM4-mediated PMN-MDSC activity involved the NF-κB/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-κB/PTGS2 pathway promoted PMN-MDSC recruitment, which played an essential role in the maintenance of intestinal homeostasis, but showed resistance to anti-PD1 therapy in CRC.

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.