Thymic stromal lymphopoietin is a key cytokine for the immunomodulation of atherogenesis with Freund's adjuvant

Abstract

Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E‐deficient (ApoE−/−) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7‐like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti‐atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1β at the site of injection. In male mice, CFA‐induced TSLP occurred in immigrated monocytes—and not epithelial cells—and was dependent on NLRP3 inflammasome activation and IL1β‐signalling. In females, CFA‐induced TSLP was independent of IL1β and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR−/− mice, with increased INFγ/IL4 ratio compared with wild‐type controls. To test whether TSLP contributes to the anti‐atherogenic effects of Freund's adjuvant, we treated ApoE−/− and ApoE−/−/TSLPR−/− mice with either CFA/IFA or PBS. ApoE−/− mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE−/−/TSLPR−/− mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune‐modulating effects via TSLP induction. TSLP‐TSLPR signalling is critical for CFA/IFA‐mediated attenuation of atherosclerosis.

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2

“…Since mice with ApoE gene knockdown are prone to abnormal lipid metabolism and lipid deposition, a large number of previous studies have used ApoE knockout (ApoE −/− ) mice for the establishment of an atherosclerotic model. 28 , 29 In this study, ApoE −/− mice were fed with normal diet (ND) or high-fat diet (HFD) for 12 weeks to study the role of miR-224-3p in atherosclerotic mice. The results of qRT-PCR and western blot analysis revealed that miR-224-3p expression was significantly upregulated, while FOSL2 expression was downregulated, and HDAC1 and HIF1α expression was unaffected in aortic tissues of ND-fed mice injected with miR-224-3p compared with mice treated with NC.…”

Elevated Plasma Thymic Stromal Lymphopoietin After Acute Myocardial Infarction

“…In contrast, Yu and co-workers reported that the expression of TSLP in the cardiovascular tissue of ApoE–/– mice was inhibited, and treatment with TSLP could prevent the development of atherosclerosis in these mice ( 11 ). Steinmetz et al showed that TSLP/TSLPR signaling also mediated the atheroprotective effect of Freund's adjuvant in ApoE–/– mice ( 17 ). The protective effect of TSLP on atherosclerosis may be related to the down-regulation of systemic inflammation.…”

Friend or foe of innate lymphoid cells in inflammation‐associated cardiovascular disease

“…IL‐4 from activated ILC2s functionally antagonizes the production of allergen‐specific Treg, while atherosclerosis is exacerbated significantly for Treg depletion 121,122 . Another study demonstrates that thymic stromal lymphopoietin plays a protective role in atherosclerosis that is mainly associated with reducing the macrophage infiltration and increasing lesional Treg 123,124 …”