YB‐1 orchestrates onset and resolution of renal inflammation via IL10 gene regulation

Abstract

The Y‐box‐binding protein (YB)‐1 plays a non‐redundant role in both systemic and local inflammatory response. We analysed YB‐1‐mediated expression of the immune regulatory cytokine IL‐10 in both LPS and sterile inflammation induced by unilateral renal ischaemia–reperfusion (I/R) and found an important role of YB‐1 not only in the onset but also in the resolution of inflammation in kidneys. Within a decisive cis‐regulatory region of the IL10 gene locus, the fourth intron, we identified and characterized an operative YB‐1 binding site via gel shift experiments and reporter assays in immune and different renal cells. In vivo, YB‐1 phosphorylated at serine 102 localized to the fourth intron, which was paralleled by enhanced IL‐10 mRNA expression in mice following LPS challenge and in I/R. Mice with half‐maximal expression of YB‐1 (Yb1 +/−) had diminished IL‐10 expression upon LPS challenge. In I/R, Yb1 +/− mice exhibited ameliorated kidney injury/inflammation in the early‐phase (days 1 and 5), however showed aggravated long‐term damage (day 21) with increased expression of IL‐10 and other known mediators of renal injury and inflammation.In conclusion, these data support the notion that there are context‐specific decisions concerning YB‐1 function and that a fine‐tuning of YB‐1, for example, via a post‐translational modification regulates its activity and/or localization that is crucial for systemic processes such as inflammation.

The Role of Y-Box Binding Protein 1 in Kidney Injury: Friend or Foe?

“…Furthermore, half-maximal expression of YB-1 led to diminished IL-10 expression upon LPS challenge, consistent with the results of a previous study [6]. However, higher YB-1 expression enhanced IL-10 mRNA expression [10]. Therefore, YB-1 exhibits both pro- and anti-inflammatory properties via IL10 gene regulation.…”

“…Regulatory T cell-derived IL-10 plays an important renoprotective role in murine models of ischaemia-reperfusion (I/R) [24]. However, Wang et al [10] found that mice with half-maximal expression of YB-1 (Yb1 +/- ) exhibited an ameliorated inflammatory response and kidney damage at the earlier stages (days 1 and 5) of I/R with aggravated kidney injury, inflammation, and less regeneration at later stages (day 21). Moreover, YB-1 was phosphorylated at serine 102 localised to the fourth intron, the IL10 gene locus, which was paralleled by enhanced IL-10 mRNA expression in mice following lipopolysaccharide (LPS) challenge and I/R.…”

“…Recently, increasing evidence has shown that YB-1 plays a protective role in acute or chronic kidney injury [6, 10]. Furthermore, YB-1 may be involved in the pathogenesis of obesity-related kidney disease (ORKD) [11].…”

Development of a novel conditional knockdown mouse based on YB‐1 protein degradation

“…YB‐1 is important in modulating inflammatory pathways including both pro‐ and anti‐inflammatory pathways, as well as repair (Hanssen et al, ; Wang et al, ). Transient upregulation of YB‐1 occurs in kidney and in heart recovering from ischemia‐reperfusion (I/R) injury during the acute phase of inflammation in experimental inflammation models.…”

“…This in vivo regulation is achieved by fusing the transgene product with a destabilizing domain, which makes the fusion protein unstable and prone to proteasome degradation; degradation can be avoided by treatment with TMP ligand. YB-1 is important in modulating inflammatory pathways including both pro-and anti-inflammatory pathways, as well as repair (Hanssen et al, 2013;Wang et al, 2017). Transient upregulation of YB-1 occurs in kidney and in heart recovering from ischemia-reperfusion (I/R) injury during the acute phase of inflammation in experimental inflammation models.…”