Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 307, Issue 11, Pages H1634-H1642Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00896.2013
Keywords
Notch 1; monocytes; macrophages; polarization; atherosclerosis
Funding
- [RO1-HL-090646]
- [HL-117241]
- [R01-HL-117241]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL090646, R01HL117241] Funding Source: NIH RePORTER
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Macrophage polarization is emerging as an important area of research for the development of novel therapeutics to treat inflammatory diseases. Within the current study, the role of Notch1R in macrophage differentiation was investigated as well as downstream effects in THP-1 monocytes cultured in inflammation mimicry media. Interference of Notch signaling was achieved using either the pharmaceutical inhibitor DAPT or Notch1R small interfering RNA (siRNA), and Notch1R expression, macrophage phenotypes, and anti-and proinflammatory cytokine expression were evaluated. Data presented show that Notch1R expression on M1 macrophages as well as M-1 macrophage differentiation is significantly elevated during cellular stress (P < 0.05). However, under identical culture conditions, interference to Notch signaling via Notch1R inhibition mitigated these results as well as promoted M-2 macrophage differentiation. Moreover, when subjected to cellular stress, macrophage secretion of proinflammatory cytokines was significantly heightened (P < 0.05). Importantly, Notch1R inhibition not only diminished proinflammatory cytokine secretion but also enhanced anti-inflammatory protein release (P < 0.05). Our data suggest that Notch1R plays a pivotal role in M-1 macrophage differentiation and heightened inflammatory responses. Therefore, we conclude that inhibition of Notch1R and subsequent downstream signaling enhances monocyte to M-2 polarized macrophage outcomes and promotes anti-inflammatory mediation during cellular stress.
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