Journal
JCI INSIGHT
Volume 6, Issue 19, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.152511
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Funding
- (NIH) /National Heart, Lung, and Blood Institute [HL131460, HL132399, HL138749, HL147565, HL130233, DK104116, DK113775]
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IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4(+)Foxp3(+) Tregs in the spleen and aorta of ApoE(-/-) mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35-deficient (IL-35P35-deficient) mice on an ApoE(-/-) background and found Treg reduction in the spleen and aorta compared with ApoE(-/-) controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE(-/-) Tregs, and we have validated higher CCR5 expression in ApoE(-/-) Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5(+) Tregs in ApoE(-/-) have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5(+) Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
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