Type 1 innate lymphoid cell aggravation of atherosclerosis is mediated through TLR4

Abstract

ILC populations elaborate a similar cytokine expression pattern with helper T cell subsets Th1, Th2 and Th17. Recent studies indicate that CD25+ILC2 could alleviate atherosclerosis by altering lipid metabolism, whereas the depletion of CD90-expressing ILCs had no influence on atherosclerosis. Thus, these findings raise the question of whether ILC1 cells react on atherosclerosis. Hence, our group attempted to explore the role of ILC1 cells in atherosclerosis. We found that ILC1 cells have a high Th1-like gene expression of T-bet and IFN-γ, which is distinct from ILC2, ILC3 or conventional NK (cNK) cells. Moreover, atherosclerotic lesions were greatly reduced in ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs for depleting ILC1 cells (ILC1+cNK cells), compared to ApoE-/-Rag1-/- mice treated with anti-IL-15R mAbs for depleting cNK cells, and these effects could be fully rescued through the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4+/+ mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs. However, the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4-/- mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs blocked the progression of atherosclerosis, indicating that the pro-atherosclerotic role of ILC1 cells is dependent on TLR4. Furthermore, oxLDL-induced increase in IFN-γ expression from ApoE-/- ILC1 cells was correlated with the decrease in BACH2 expression. Taken together, ILC1 cells exist in atherosclerosis and aggravate atherosclerosis via increasing pro-inflammatory cytokine expression in a TLR4/BACH2-dependent manner.

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

“…A lot of studies have shown that plaque burden decreased in the atherosclerosis mice model lacking T‐bet, IFN‐γ and IL‐12, indicating the relationship between Th1 and atherosclerosis 112–114 . As a mirror cell of Th1, ILC1s sorted from the spleen of ApoE −/− TLR4 +/+ mice are transferred into ApoE −/− Rag1 −/− mice with anti‐NK1.1 mAbs for depleting ILC1 cells and aggravate atherosclerosis, whereas ILC1s from ApoE −/− TLR4 −/− mice block the progression of atherosclerosis, and the size of atherosclerotic plaque in ApoE −/− Rag1 −/− mice with the knockdown of ILC1s is smaller than that in NKs knockdown mice 115 . ILC1s in atherosclerosis express CD127, IFN‐γ, T‐bet, IL‐6 and IL‐1β, but lack c‐Kit, CD34, GATA‐3 and RORγt, distinct with NK cells 116 .…”

“…The increase of IFN‐γ produced by ILC1 in ApoE −/− mice induced by oxLDL is related to the decrease of Bach2 expression. ILC1s respond to atherosclerosis danger signals may convey by the signalling pathway of TLR4/BACH2, which has significant effects on atherosclerosis in the early stage 115 …”

MiR-31 promotes Th22 differentiation through targeting Bach2 in coronary heart disease

“…Bach2 was required for stabilizing the Treg-mediated immune homeostasis through repressing the differentiation programs of multiple effector lineages in CD4 + T cells [20]. Accumulating evidence has shown that Bach2 plays important roles in the differentiation of Th1, Th2, and Th17 cells by inhibiting the expression of T-lymphocyte transcription factors such as GATA3 and IRF4 [21–23]. Bach2-deficient T cells show spontaneous activation and produce high levels of Th1/Th2-type cytokines.…”

T‐bet transcription factor in cardiovascular disease: Attenuation or inflammation factor?

“…In several CVDs, including heart failure (HF) and atherosclerosis, inflammation leads to the progression of disease by impairing cardiac cells and activating effector immune cells (e.g., TCD4 + ), which causes the release of different chemokines and cytokines (Haybar, Shahrabi, Rezaeeyan, Shirzad, & Saki, ; Su et al, ; Zhao et al, ). Innate and adaptive immune responses are involved in the activation of T‐cells (Wu et al, ), and TCD4 + cells are seemingly the most important cells that play a role in CVD pathogenesis. However, the differentiation rate of T‐cells to T helper1 (Th1) or Th2 cells is likely to determine the degree of disease progression (Li et al, ).…”