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The Role of Notch Signaling in Macrophages during Inflammation and Infection: Implication in Rheumatoid Arthritis?

ABSTRACT: Notch signaling coordinates numerous cellular processes and has been implicated in many pathological conditions, including rheumatoid arthritis (RA). Although the role of Notch signaling in development, maturation, differentiation, and activation of lymphocytes has been comprehensively reported, less is known about its role in myeloid cells. Certainly, limited data are available about the role of Notch signaling in macrophages during inflammation and infection. In this review, we discuss the recent advances pertaining to the role of Notch signaling in differentiation, activation, and metabolism of macrophages during inflammation and infection. We also highlight the reciprocal interplay between Notch signaling and other signaling pathways in macrophages under different inflammatory and infectious conditions including pathogenesis of RA. Finally, we discuss approaches that could consider Notch signaling as a potential therapeutic target against infection- and inflammation-driven diseases.

SUBMITTER: Keewan E

PROVIDER: S-EPMC7016800 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The Role of Notch Signaling in Macrophages during Inflammation and Infection: Implication in Rheumatoid Arthritis?

Keewan Esra'a E Naser Saleh A SA

Cells 20200102 1

Notch signaling coordinates numerous cellular processes and has been implicated in many pathological conditions, including rheumatoid arthritis (RA). Although the role of Notch signaling in development, maturation, differentiation, and activation of lymphocytes has been comprehensively reported, less is known about its role in myeloid cells. Certainly, limited data are available about the role of Notch signaling in macrophages during inflammation and infection. In this review, we discuss the rec ...[more]

PMID: 31906482

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Project description:ObjectiveSubclinical joint inflammation in patients with arthralgia is predictive for progression to rheumatoid arthritis (RA). However, the time course of progression for bone marrow edema (osteitis), synovitis, and/or tenosynovitis is unsettled. This longitudinal study assessed the course of magnetic resonance imaging (MRI)-detected subclinical joint inflammation during progression to RA.MethodsPatients that progressed from clinically suspect arthralgia (CSA) to RA underwent 1.5-T MRI of the metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints at presentation with arthralgia and at first identification of synovitis assessed through physical examination (n?=?31). MRIs were evaluated for osteitis, synovitis, tenosynovitis, and erosions by two readers, blinded for clinical data and order in time. To estimate changes in MRI scores between the asymptomatic state and CSA onset, scores of MRI features at CSA baseline were compared with scores from age-matched symptom-free persons.ResultsAt presentation with CSA, synovitis and tenosynovitis scores were higher than scores from age-matched symptom-free persons (p?=?0.004 and p?=?0.001, respectively). Anti-citrullinated protein antibody (ACPA)-positive arthralgia patients also had increased osteitis scores (p?=?0.04). Median duration between presentation with arthralgia and RA development was 17 weeks. During progression to RA, synovitis and osteitis increased significantly (p?=?0.001 and p?=?0.036, respectively) in contrast to tenosynovitis and erosion scores. This pattern was similar in both ACPA subsets, although statistical significance was reached for synovitis and osteitis in ACPA-negative but not ACPA-positive RA.ConclusionIncreased tenosynovitis and synovitis scores at CSA onset and the increase in synovitis and osteitis during progression to RA suggest an 'outside-in' temporal relationship of arthritis development, in particular for ACPA-negative RA. For ACPA-positive RA, further studies are needed.

Project description:Notch signaling pathways exert effects throughout pregnancy and are activated in response to TLR ligands. To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta-like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed. Preterm labor was initiated on gestation d 14.5 by 1 of 2 methods: 1) inflammation-induced preterm labor: intrauterine injection of LPS (a TLR4 agonist) and 2) hormonally induced preterm labor: subcutaneous injection of mifepristone. Delta-like protein-1, Notch1, and hairy and enhancer of split-1 were elevated significantly, and Numb was decreased in the uterus and placenta of inflammation-induced preterm labor mice but remained unchanged in hormonally induced preterm labor compared with their respective controls. F4/80(+) macrophage polarization was skewed in the uterus of inflammation-induced preterm labor toward M1-positive (CD11c(+)) and double-positive [CD11c(+) (M1) and CD206(+) (M2)] cells. This process is dependent on activation of Notch signaling, as shown by suppression of M1 and M2 macrophage-associated cytokines in decidual macrophages in response to ?-secretase inhibitor (an inhibitor of Notch receptor processing) treatment ex vivo. ?-Secretase inhibitor treatment also diminished the LPS-induced secretion of proinflammatory cytokines and chemokines in decidual and placental cells cultured ex vivo. Furthermore, treatment with recombinant Delta-like protein-1 ligand enhanced the LPS-induced proinflammatory response. Notch ligands (Jagged 1 and 2 and Delta-like protein-4) and vascular endothelial growth factor and its receptor involved in angiogenesis were reduced significantly in the uterus and placenta during inflammation-induced preterm labor. These results suggest that up-regulation of Notch-related inflammation and down-regulation of angiogenesis factors may be associated with inflammation-induced preterm labor but not with hormonally induced preterm labor.

Dataset Information

The Role of Notch Signaling in Macrophages during Inflammation and Infection: Implication in Rheumatoid Arthritis?

Publications

The Role of Notch Signaling in Macrophages during Inflammation and Infection: Implication in Rheumatoid Arthritis?

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