OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment.

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.

Corrigendum: Endothelin-A Receptor Antagonist Alleviates Allergic Airway Inflammation via the Inhibition of ILC2 Function.

[This corrects the article DOI: 10.3389/fimmu.2022.835953.].

Endothelin-A Receptor Antagonist Alleviates Allergic Airway Inflammation via the Inhibition of ILC2 Function.

Allergic airway inflammation is a universal airway disease that is driven by hyperresponsiveness to inhaled allergens. Group 2 innate lymphoid cells (ILC2s) produce copious amounts of type 2 cytokines, which lead to allergic airway inflammation. Here, we discovered that both peripheral blood of human and mouse lung ILC2s express the endothelin-A receptor (ETAR), and the expression level of ETAR was dramatically induced upon interleukin-33 (IL-33) treatment. Subsequently, both preventive and therapeutic effects of BQ123, an ETAR antagonist, on allergic airway inflammation were observed, which were associated with decreased proliferation and type 2 cytokine productions by ILC2s. Furthermore, ILC2s from BQ123 treatment were found to be functionally impaired in response to an interleukin IL-33 challenged. And BQ123 treatment also affected the phosphorylation level of the extracellular signal-regulated kinase (ERK), as well as the level of GATA binding protein 3 (GATA3) in activated ILC2s. Interestingly, after BQ123 treatment, both mouse and human ILC2s in vitro exhibited decreased function and downregulation of ERK signaling and GATA3 stability. These observations imply that ETAR is an important regulator of ILC2 function and may be involved in ILC2-driven pulmonary inflammation. Therefore, blocking ETAR may be a promising therapeutic strategy for allergic airway inflammation.

Polymorphonuclear myeloid-derived suppressor cells link inflammation and damage response after trauma.

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-ß1 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.

Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development.

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.

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation.

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.