Retinal ganglion cells (RGC) play a crucial role in the visual pathway. As their axons form the optic nerve, apoptosis of these cells causes neurodegenerative vision loss. RGC death could be triggered by increased intraocular pressure, advanced glycation end products, or mitochondrial dysfunction. In this review, we summarize the role of some neuroprotective factors in RGC injury: ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), glial cell line-derived neurotrophic factor (GDNF), and Norrin. Each, in their own unique way, prevents RGC damage caused by glaucoma, ocular hypertension, ischemic neuropathy, and even oxygen-induced retinopathy. These factors are produced mainly by neurons, leukocytes, glial cells, and epithelial cells. Neuroprotective factors act via various signaling pathways, including JAK/STAT, MAPK, TrkA, and TrkB, which promotes RGC survival. Many attempts have been made to develop therapeutic strategies using these factors. There are ongoing clinical trials with CNTF and NGF, but they have not yet been accepted for clinical use.

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced L-arginine depletion suppresses T-cell responses. In humans with anemia, CECs expand and express ARG1 and ARG2 that suppress T-cells IFN-γ production. Moreover, bone marrow CECs from healthy human donors suppress T-cells proliferation. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-γ production in an ARG- and ROS-dependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The suppressive properties disappear during erythroid differentiation as more differentiated CECs and mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of CECs in the immune response regulation.

Erythroid progenitor cells (EPCs) have been recently recognized as potent immunoregulatory cells with defined roles in fetomaternal tolerance and immune response to infectious agents in neonates and cancer patients. Here, we show that early-stage EPCs are enriched in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). EPCs expansion in anemic mice leads to the L-arginine depletion in the spleen microenvironment resulting in the suppression of T-cell responses. In humans with anemia, EPCs expand and express both ARG1 and ARG2 that participate in suppressing the proliferation and production of IFN-γ from T-cells. EPCs differentiated from peripheral blood mononuclear cells potently suppress T-cell proliferation and this effect is the most prominent for CD49dhi CD71hiEPCs. The suppressive properties disappear during erythroid differentiation as more differentiated EPCs as well as mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of EPCs in the regulation of immune response.Abstract Figure

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