A Crucial Role of CXCL14 for Promoting Regulatory T Cells Activation in Stroke

Abstract

Inflammatory processes have a detrimental role in the pathophysiology of ischemic stroke. However, little is known about the endogenous anti-inflammatory mechanisms in ischemic brain. Here, we identify CXCL14 as a critical mediator of these mechanisms. CXCL14 levels were upregulated in the ischemic brains of humans and rodents. Moreover, hypoxia inducible factor-1α (HIF-1α) drives hypoxia- or cerebral ischemia (CI)-dependent CXCL14 expression via directly binding to the CXCL14 promoter. Depletion of CXCL14 inhibited the accumulation of immature dendritic cells (iDC) or regulatory T cells (Treg) and increased the infarct volume, whereas the supplementation of CXCL14 had the opposite effects. CXCL14 promoted the adhesion, migration, and homing of circulating CD11c+ iDC to the ischemic tissue via the upregulation of the cellular prion protein (PrPC), PECAM-1, and MMPs. The accumulation of Treg in ischemic areas of the brain was mediated through a cooperative effect of CXCL14 and iDC-secreted IL-2-induced Treg differentiation. Interestingly, CXCL14 largely promoted IL-2-induced Treg differentiation. These findings indicate that CXCL14 is a critical immunomodulator involved in the stroke-induced inflammatory reaction. Passive CXCL14 supplementation provides a tractable path for clinical translation in the improvement of stroke-induced neuroinflammation.

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

“…In addition, TGF‐β is unlikely the only cytokine that promotes Treg accumulation in hypoxic tumor. In a study of Treg activation by ischemic stroke, HIF‐1α was shown to bind the CXCL14 promoter and drive hypoxia‐dependent CXCL14 expression, with CXCL14 promoting the accumulation of Tregs in the ischemic brain . This study has revealed a new mechanism by which HIF‐1α expression in hypoxic brain cells leads to Tregs recruitment.…”

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

“…Lee et al . also suggested that CXCL14 can promote Treg differentiation and activation . In contrast, Kleinshnitz et al .…”

“…108 Lee et al also suggested that CXCL14 can promote Treg differentiation and activation. 109 In contrast, Kleinshnitz et al surprisingly showed that depletion of Treg cells using the DEREG mouse model reduces brain infarct size, suggesting that Treg cells can further brain damage by inducing BBB dysfunction. 110 Currently, the Treg cell contribution to ischaemic brain damage is still a highly debated topic.…”

Differences in gene expression profiling and biomarkers between histological colorectal carcinoma subsets from the serrated pathway

“…We decided to validate it by using qPCR and IHC, and showed concordance between the array results and the results obtained with these two techniques. This cytokine is implicated in the homeostasis of monocyte‐derived macrophages rather than in inflammation and in recruitment of immature dendritic cells and regulatory T cells and in blocking of endothelial cell chemotaxis . Moreover, hypoxia‐inducible factor‐1α and nitric oxide synthase 1 (NOS1) activate CXCL14, whereas inflammatory stimuli such as bacterial lipopolysaccharides block CXCL14 activity .…”

“…This cytokine is implicated in the homeostasis of monocyte-derived macrophages rather than in inflammation and in recruitment of immature dendritic cells and regulatory T cells and in blocking of endothelial cell chemotaxis. [32][33][34] Moreover, hypoxia-inducible factor-1a and nitric oxide synthase 1 (NOS1) activate CXCL14, 35 whereas inflammatory stimuli such as bacterial lipopolysaccharides block CXCL14 activity. 36,37 Taken together, these findings suggest that antiangiogenic therapy 38 or NOS1 inhibitors could be potential therapeutic approaches for activating the immune system against SAC.…”