NOTCH3 signaling is essential for NF-κB activation in TLR-activated macrophages

Abstract

Macrophage activation by Toll receptors is an essential event in the development of the response against pathogens. NOTCH signaling pathway is involved in the control of macrophage activation and the inflammatory processes. In this work, we have characterized NOTCH signaling in macrophages activated by Toll-like receptor (TLR) triggering and determined that DLL1 and DLL4 are the main ligands responsible for NOTCH signaling. We have identified ADAM10 as the main protease implicated in NOTCH processing and activation. We have also observed that furin, which processes NOTCH receptors, is induced by TLR signaling in a NOTCH-dependent manner. NOTCH3 is the only NOTCH receptor expressed in resting macrophages. Its expression increased rapidly in the first hours after TLR4 activation, followed by a gradual decrease, which was coincident with an elevation of the expression of the other NOTCH receptors. All NOTCH1, 2 and 3 contribute to the increased NOTCH signaling detected in activated macrophages. We also observed a crosstalk between NOTCH3 and NOTCH1 during macrophage activation. Finally, our results highlight the relevance of NOTCH3 in the activation of NF-κB, increasing p65 phosphorylation by p38 MAP kinase. Our data identify, for the first time, NOTCH3 as a relevant player in the control of inflammation.

Impact of Fetal Growth Restriction on the Neonatal Microglial Proteome in the Rat

“…Protein sets associated with body weight were, indeed, significantly enriched in LPD microglia at both time points, and we observed deregulation of proteins involved in the modulation of body weight in both P1 and P4 LPD microglia, with a tendency toward reversal of the effect observed at P1 in P4 microglia. The analysis revealed a role of the differentially expressed proteins in the modulation of important biological processes, such as apoptosis and modulation of the NOTCH3 signaling transduction pathway, which has been recently reported to be essential for the positive modulation of the pro-inflammatory transcription factor NFkB in macrophages [50]. This is the first evidence of an association between the IUGR phenotype and the microglial proteome.…”

SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes

“…Notch is also associated with NF-κB activation, and its role in inflammatory response was documented while blocking the Notch signaling correspond to reduced inflammation and impaired NF-κB activation [ 48 ]. Another work in activated macrophages connects TLRs action, Notch3 activation, and NF-κB activity, and the selective silencing of Notch3 inhibits the activity of NF-κB [ 49 ]. Translating this evidence in our study, ELISA tests on the conditioned medium highlight the difference between the secretion of IL-6 and proinflammatory cytokines between MSCs-lung and MSCs-CPAM, while the first group showed increased NOTCH3 value and the second suggest a block of Notch signaling.…”

Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders

“…Notch3 is primarily found in developing T cells, vascular smooth muscle and pericytes, and Notch4 in the endothelium. However, recent work reported new functional roles for Notch3 and Notch4 in other cells relevant to immune disorders such as synovial fibroblasts and macrophages for Notch3, and regulatory T cells for Notch4 (Harb et al, 2020;Lopez-Lopez et al, 2020;Wei et al, 2020). Notch receptors are single-pass transmembrane proteins with variations primarily in their extracellular ligand binding and intracellular signaling domains (Figure 1).…”