Why splenic HSPCs and committed myeloid precursors are more sensitive than their BM counterparts to such treatments is presently unclear

Why splenic HSPCs and committed myeloid precursors are more sensitive than their BM counterparts to such treatments is presently unclear. from the spleen and compromises splenic EMH (120). On the other hand, macrophages can regulate splenic EMH by phagocytosing redundant HSPCs in the spleen. According to an early study, the phagocytosis of HSPCs by the numerous active macrophages present in the cords of the red pulp results in limited EMH in human spleens (121), suggesting that phagocytosis is usually a key mechanism regulating splenic HSPC activity. CD47 is usually a don’t eat me signal that inhibits phagocytosis by binding to its receptor signal regulatory protein (SIRP), which is usually expressed on phagocytes. HSPCs upregulate CD47 expression just before and during their migration to the periphery to avoid inappropriate phagocytosis (122). Thus, the downregulation of CD47 GO6983 expression might lead to the clearance of splenic HSPCs as they age or become dysfunctional. Therefore, macrophages could play dual roles in GO6983 modulating splenic EMH. However, the roles that splenic macrophages play in regulating cancer-induced splenic EMH during cancer development and the relationship between these functions are still largely unknown. Since therapies targeting macrophages (21, 32, 123) and anti-CD47 treatment (122, 124, 125) are emerging as novel anti-tumor strategies, a deeper understanding of these issues may reveal the impact of these treatments on splenic EMH. The Nervous System and Neural Signal-Expressing Cells Recent studies GO6983 have revealed an intricate, panicle-shaped sympathetic architecture in the spleen (126). Most detectable nerves entering the spleen arise from the nerve plexus that surrounds branches of the splenic artery and are catecholaminergic (127). Such sympathetic architecture is usually absent in the other classic lymphoid organs, but whether and how this unique innervation of the spleen contributes to the distinct EMH remains largely unclear. A recent study showed that in liver cancer models, blocking -adrenergic signaling could prevent the redistribution of splenic myeloid cells and inhibit tumor growth induced by restraint stress Rabbit Polyclonal to DNAI2 (128). In addition, immune cells such as macrophages and T cells can also produce catecholamines (129, 130). Although data from cancer models are limited, in hyperglycemic conditions, the spleens of diabetic patients and mice harbor increased numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produce catecholamines, and GMPs that are actively proliferating. These two events are closely linked, as the interaction of catecholamine and 2 adrenergic receptors expressed on splenic GMPs mediates GMP proliferation and myeloid cell production. Moreover, TH+ leukocytes are located close to splenic nerves and express high levels of neuropeptide Y receptors, suggesting that these cells are involved in neuroimmune communication (90). These mechanisms may also exist in cancer-bearing hosts. Future studies are required to identify the roles of the nervous system and neural signal-expressing cells in regulating cancer-induced myelopoiesis. Signals From Distant Organs Although it is almost certain that tumors can profoundly affect splenic myelopoiesis, either directly or indirectly, as the tumor influences the BM (65), the molecular mechanisms remain largely undetermined. In the scenario of cancers expressing high levels of CSFs, these cytokines may be the major cause of HSPC mobilization, splenomegaly, and vigorous splenic myelopoiesis (36, 97, 131, 132). In addition to hematopoietic cytokines, other tumor-derived factors, e.g., peptides and carbohydrates, can also impact on HSPC behaviors. Cortez-Retamozo et al. showed angiotensin II (AngII), a peptide hormone that belongs to the renin-angiotensin system, may also play a significant role in HSPC retention (98). They found that the expression of angiotensinogen, the AngII precursor, was upregulated in a mouse model of lung adenocarcinoma as well as in human lung cancer stroma. AngII could directly induce HSPC amplification in the splenic red pulp, suppressing.