The Notch signaling pathway controls CD8+ T cell differentiation independently of the classical effector HES1.

During CD8+ T cell response, Notch signaling controls short-lived-effector-cell (SLEC) generation, but the exact mechanisms by which it does so remains unclear. The Notch signaling pathway can act as a key regulator of Akt signaling via direct transcriptional induction of Hes1, which will then repress the transcription of Pten, an inhibitor of Akt signaling. As both Notch and Akt signaling can promote effector CD8+ T cell differentiation, we asked whether Notch signaling influences SLEC differentiation via the HES1-PTEN axis. Here, we demonstrate that HES1 deficiency in murine CD8+ T cells did not impact SLEC differentiation. Moreover, we show that Pten transcriptional repression in effector CD8+ T cells is not mediated by Notch signaling although Akt activation requires Notch signaling. Therefore, HES1 is not an effector of Notch signaling during CD8+ T cell response.

Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/reperfusion injury in the kidney.

The cholinergic anti-inflammatory pathway (CAP) links the nervous and immune systems and modulates innate and adaptive immunity. Activation of the CAP by vagus nerve stimulation exerts protective effects in a wide variety of clinical disorders including rheumatoid arthritis and Crohn's disease, and in murine models of acute kidney injury including ischemia/reperfusion injury (IRI). The canonical CAP pathway involves activation of splenic alpha7-nicotinic acetylcholine receptor (α7nAChR)-positive macrophages by splenic ß2-adrenergic receptor-positive CD4+ T cells. Here we demonstrate that ultrasound or vagus nerve stimulation also activated α7nAChR-positive peritoneal macrophages, and that adoptive transfer of these activated peritoneal macrophages reduced IRI in recipient mice. The protective effect required α7nAChR, and did not occur in splenectomized mice or in mice lacking T and B cells, suggesting a bidirectional interaction between α7nAChR-positive peritoneal macrophages and other immune cells including ß2-adrenergic receptor-positive CD4+ T cells. We also found that expression of hairy and enhancer of split-1 (Hes1), a basic helix-loop-helix DNA-binding protein, is induced in peritoneal macrophages by ultrasound or vagus nerve stimulation. Adoptive transfer of Hes1-overexpressing peritoneal macrophages reduced kidney IRI. Our data suggest that Hes1 is downstream of α7nAChR and is important to fully activate the CAP. Taken together, these results suggest that peritoneal macrophages play a previously unrecognized role in mediating the protective effect of CAP activation in kidney injury, and that Hes1 is a new candidate pharmacological target to activate the CAP.

Fluvoxamine stimulates oligodendrogenesis of cultured neural stem cells and attenuates inflammation and demyelination in an animal model of multiple sclerosis.

Multiple Sclerosis (MS) require medications controlling severity of the pathology and depression, affecting more than half of the patients. In this study, the effect of antidepressant drug fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in vitro and in vivo. Nanomolar concentrations of fluvoxamine significantly increased cell viability and proliferation of neural stem cells (NSCs) through increasing mRNA expression of Notch1, Hes1 and Ki-67, and protein levels of NICD. Also, physiological concentrations of fluvoxamine were optimal for NSC differentiation toward oligodendrocytes, astrocytes and neurons. In addition, fluvoxamine attenuated experimental autoimmune encephalomyelitis (EAE) severity, a rat MS model, by significantly decreasing its clinical scores. Moreover, fluvoxamine treated EAE rats showed a decrease in IFN-γ serum levels and an increase in IL-4, pro- and anti-inflammatory cytokines respectively, compared to untreated EAE rats. Furthermore, immune cell infiltration and demyelination plaque significantly decreased in spinal cords of fluvoxamine-treated rats, which was accompanied by an increase in protein expression of MBP and GFAP positive cells and a decrease in lactate serum levels, a new biomarker of MS progression. In summary, besides its antidepressant activity, fluvoxamine stimulates proliferation and differentiation of NSCs particularly toward oligodendrocytes, a producer of CNS myelin.

Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway.

As the most important host defence against viral infection, interferon (IFN) stimulates hundreds of antiviral genes (ISGs) that together establish an 'antiviral state'. However, the antiviral function of most ISGs in viral infection still need further exploration. Here, we demonstrated that the expression of G-protein-coupled receptor 146 (GPR146) is highly increased by both IFN-ß and IFN-γ in a signal transducer and activator of transcription 1-dependent signalling pathway. Most importantly, overexpression of GPR146 protects the host cells from vesicular stomatitis virus and Newcastle disease virus infection but not from infection by herpes simplex virus. In contrast, the virus-induced IFN-ß production changed little in Gpr146-knockout cells. Furthermore, the Gpr146-deficient mice showed similar susceptibility to wild-type mice with vesicular stomatitis virus infection. Interestingly, the expression of GPR146 in virus-infected cells was strikingly reduced and can partially explain why the viral infection was little influenced in Gpr146-knockout mice. Surprisingly, virus-activated IFN regulatory factor 3 (IRF3) signalling not only induces the expression of IFN but also represses GPR146 expression through HES1 (hairy and enhancer of split-1)-mediated transcriptional activity to establish a dynamic equilibrium between pro-viral and antiviral stages in host cells. Taken together, these data reveal the antiviral role of GPR146 in fighting viral infection although the GPR146-mediated protection is eliminated by IRF3/HES1-signalling, which suggests a potential therapeutic significance of both GPR146 and HES1 signalling in viral infection.

HES1 in immunity and cancer.

Hairy and enhancer of split homolog-1 (HES1) is a part of an extensive family of basic helix-loop-helix (bHLH) proteins and plays a crucial role in the control and regulation of cell cycle, proliferation, cell differentiation, survival and apoptosis in neuronal, endocrine, T-lymphocyte progenitors as well as various cancers. HES1 is a transcription factor which is regulated by the NOTCH, Hedgehog and Wnt signalling pathways. Aberrant expression of these pathways is a common feature of cancerous cells. There appears to be a fine and complicated crosstalk at the molecular level between the various signalling pathways and HES1, which contributes to its effects on the immune response and cancers such as leukaemia. Several mechanisms have been proposed, including an enhanced invasiveness and metastasis by inducing epithelial mesenchymal transition (EMT), in addition to its strict requirement for tumour cell survival. In this review, we summarize the current biology and molecular mechanisms as well as its use as a clinical target in cancer therapeutics.