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.
NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
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Medientyp:
E-Artikel
Titel:
NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
Beteiligte:
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.
Erschienen:
Frontiers Media SA, 2021
Erschienen in:
Frontiers in Immunology, 12 (2021)
Sprache:
Nicht zu entscheiden
DOI:
10.3389/fimmu.2021.734966
ISSN:
1664-3224
Entstehung:
Anmerkungen:
Beschreibung:
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.