Notch Signaling in Acute Inflammation and Sepsis

Abstract

Notch signaling, a highly conserved pathway in mammals, is crucial for differentiation and homeostasis of immune cells. Besides, this pathway is also directly involved in the transmission of immune signals. Notch signaling per se does not have a clear pro- or anti-inflammatory effect, but rather its impact is highly dependent on the immune cell type and the cellular environment, modulating several inflammatory conditions including sepsis, and therefore significantly impacts the course of disease. In this review, we will discuss the contribution of Notch signaling on the clinical picture of systemic inflammatory diseases, especially sepsis. Specifically, we will review its role during immune cell development and its contribution to the modulation of organ-specific immune responses. Finally, we will evaluate to what extent manipulation of the Notch signaling pathway could be a future therapeutic strategy.

Keywords: DLL; Jagged; Notch; SIRS; immune cells; immune response; infection; inflammation; sepsis; therapy.

Figure 1

Contact dependent Notch signaling between cells. Ligand binding leads to a conformational change of the receptor. The first cleavage is arbitrated by the ADAM -family which leads to shedding of the extracellular domain. The second cleavage takes place inside the transmembrane domain and is catalyzed by a γ-secretase complex, that discharges the NICD to translocate to the nucleus. Within the nucleus, the NICD binds the DNA-binding protein RBP-J. Binding of NICD leads to transcription of the Notch target genes. Created with BioRender.com.