The YB-1:Notch-3 axis modulates immune cell responses and organ damage in systemic lupus erythematosus

Notch notches lupus

“…Another intriguing point that is raised by this study 6 and, like any good study it raises many, is why upregulation of interleukin-10, a suppressive cytokine also produced by FoxP3-negative regulatory T cells, 9 by Notch fails to suppress the autoimmune response and lupus nephritis. In parallel, it is noted that Notch deficiency in the B6.lpr mouse limits the numbers of regulatory Foxp3positive T cells.…”

“…More relevant for the purposes of this communication, however, we have no information on the possible interactions between Notch signaling and the CD3/TCR signaling processes, which are known to display distinct aberrations in patients with systemic lupus erythematosus and lupus nephritis. 5 In this issue, Breitkopf and his colleagues 6 reveal an important aspect of Notch signaling in the control of lupus nephritis to which they assign a protective role, thus opening the way for the development of agonists to prevent kidney inflammation and damage ( Figure 1). First, they report the existence at high levels of a guanidinylated form of the soluble Notch ligand YB-1 in samples (peripheral blood and kidney tissues) from both patients with lupus nephritis and lupus-prone mice.…”

“…An obvious question that is raised by the studies from Breitkopf et al 6 is why the upregulated Notch and its ligand YB-1 fail to suppress the inflammatory response. It appears that the target HES genes are expressed, and most probably the signaling process that involves an active ADAM10 and the g-secretase are not affected, although it is possible that the strength of the signal in each of the involved cells is affected.…”

The Role of Notch3 Signaling in Kidney Disease

“…Pearson correlation analyses proved that the glomerular expression of Notch3 was positively correlated with that of both Jagged and YBX1 [ 29 ]. Jagged2 is a canonical Notch ligand [ 39 ], and YBX-1, a newly identified noncanonical ligand within the Notch3 signaling framework, is characterized as a downstream target in PDGF-BB (a key cytokine that drives mesangioproliferative diseases) signaling [ 39 – 41 ]. In addition, temporally and spatially coordinated upregulation of the receptor Notch3 and the noncanonical ligand YBX-1 within the glomerular compartment was observed in a rat model of mesangioproliferative nephritis [ 42 ].…”

“…In contrast, in mouse models and patients with ADPKD, Notch3 is upregulated in cyst-lining epithelial cells. In lupus nephritis [ 41 ], rapidly progressive renal disease [ 20 ], and focal segmental glomerulonephropathy [ 34 ], Notch3 is expressed in glomerular podocytes. In summary, the identification of Notch3 target cells in the context of different types of renal injury is of vital importance.…”