Abstract
NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1. Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation.
Highlights
Inflammation is a basic defense response induced by the cells of the innate immunity, especially macrophages, against infection and tissue damage
NOTCH4, through the inhibition of IFN-g signaling, favors overall NOTCH signaling by promoting the feedback inhibitor cycle carried out by HES1 and HEY1, which decreases the production of cytokines. These results provide new insights into the mechanisms by which NOTCH, Toll-like receptors (TLR) and IFN-g signals are integrated to modulate specific effector functions in macrophages and reveal NOTCH4 as a new regulatory agent in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excessive inflammatory response
As previously described for NOTCH1 and NOTCH2, NOTCH4 was not expressed in control differentiated macrophages [9]; its expression increased in all cases about six hours after macrophage activation and remained elevated for at least 24 h (Figure 1A)
Summary
Inflammation is a basic defense response induced by the cells of the innate immunity, especially macrophages, against infection and tissue damage. Inflammation allows the recruitment of cells and triggering of effector defense mechanisms to the infectious foci to achieve their elimination. Deregulation of this process could lead to chronic or excessive inflammation. Signaling through TLRs involves the recruitment of different adaptive proteins that allow the activation of the IkB kinase complex, and mitogen activated protein kinases (MAPKs). This leads to the activation of key transcription factors, such as NF-kB, that increase the expression of pro-inflammatory cytokines [3]
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