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

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 th...

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Autores principales:	Susana López-López, María José Romero de Ávila, Natalia Carolina Hernández de León, Francisco Ruiz-Marcos, Victoriano Baladrón, María Luisa Nueda, Jorge Laborda, José Javier García-Ramírez, Eva M. Monsalve, María José M. Díaz-Guerra
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	macrophage inflammation NOTCH4 IFN-γ TLR Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/1b8d94105a284db482368c8e152f64b1
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spelling	oai:doaj.org-article:1b8d94105a284db482368c8e152f64b12021-12-01T21:37:57ZNOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling1664-322410.3389/fimmu.2021.734966https://doaj.org/article/1b8d94105a284db482368c8e152f64b12021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.734966/fullhttps://doaj.org/toc/1664-3224NOTCH4 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.Susana López-LópezMaría José Romero de ÁvilaNatalia Carolina Hernández de LeónFrancisco Ruiz-MarcosVictoriano BaladrónMaría Luisa NuedaJorge LabordaJosé Javier García-RamírezEva M. MonsalveMaría José M. Díaz-GuerraFrontiers Media S.A.articlemacrophageinflammationNOTCH4IFN-γTLRImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	macrophage inflammation NOTCH4 IFN-γ TLR Immunologic diseases. Allergy RC581-607
spellingShingle	macrophage inflammation NOTCH4 IFN-γ TLR Immunologic diseases. Allergy RC581-607 Susana López-López María José Romero de Ávila Natalia Carolina Hernández de León Francisco Ruiz-Marcos Victoriano Baladrón María Luisa Nueda Jorge Laborda José Javier García-Ramírez Eva M. Monsalve María José M. Díaz-Guerra NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
description	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.
format	article
author	Susana López-López María José Romero de Ávila Natalia Carolina Hernández de León Francisco Ruiz-Marcos Victoriano Baladrón María Luisa Nueda Jorge Laborda José Javier García-Ramírez Eva M. Monsalve María José M. Díaz-Guerra
author_facet	Susana López-López María José Romero de Ávila Natalia Carolina Hernández de León Francisco Ruiz-Marcos Victoriano Baladrón María Luisa Nueda Jorge Laborda José Javier García-Ramírez Eva M. Monsalve María José M. Díaz-Guerra
author_sort	Susana López-López
title	NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
title_short	NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
title_full	NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
title_fullStr	NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
title_full_unstemmed	NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling
title_sort	notch4 exhibits anti-inflammatory activity in activated macrophages by interfering with interferon-γ and tlr4 signaling
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1b8d94105a284db482368c8e152f64b1
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NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling

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