NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling

• Published in: Frontiers in immunology Vol. 12; p. 734966
• Main Authors: López-López, Susana, Romero de Ávila, María José, Hernández de León, Natalia Carolina, Ruiz-Marcos, Francisco, Baladrón, Victoriano, Nueda, María Luisa, Laborda, Jorge, García-Ramírez, José Javier, Monsalve, Eva M, Díaz-Guerra, María José M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 01-12-2021
• Subjects: Animals; Blood Donors; Humans; IFN-γ; Immunology; inflammation; Interferon-gamma - metabolism; Lipopolysaccharides - pharmacology; macrophage; Macrophage Activation - genetics; Macrophages, Peritoneal - immunology; Male; Mice; Mice, Inbred C57BL; Monocytes - metabolism; NOTCH4; RAW 264.7 Cells; Receptor, Notch4 - genetics; Receptor, Notch4 - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; TLR; Toll-Like Receptor 4 - metabolism; Transfection; macrophage; IFN-γ; TLR; inflammation; NOTCH4
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.734966

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
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
. 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.