Abstract
Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL‐22, with both Th22 cells and IL‐22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE−/− mice and age‐matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL‐22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE−/− mice fed a Western diet for 12 weeks and administered recombinant mouse IL‐22 (rIL‐22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL‐6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α‐actin expression than the control mice. Treatment with a neutralizing anti–IL‐22 monoclonal antibody (IL‐22 mAb) reversed the above effects. Bone marrow‐derived DCs exhibited increased differentiation into mature DCs following rIL‐22 and ox‐LDL stimulation. IL‐17 and pSTAT3 were up‐regulated after stimulation with IL‐22 and ox‐LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up‐regulation was significantly inhibited by IL‐6mAb or the cell‐permeable STAT3 inhibitor S31‐201. Thus, Th22 cell‐derived IL‐22 aggravates atherosclerosis development through a mechanism that is associated with IL‐6/STAT3 activation, DC‐induced Th17 cell proliferation and IL‐22–stimulated SMC dedifferentiation into a synthetic phenotype.
Highlights
Our previous study revealed significant increases in the peripheral Th22 cell numbers and IL-22 levels of patients with acute coronary syndrome (ACS) compared to patients with stable angina pectoris (SAP) and control patients, suggesting that the circulating Th22-type response may have a potential role in the onset of ACS symptoms.[23]
We observed that IL22R1 is expressed in aortic tissue and that Th22 cells are the major producers of IL-22 during the progression of AS
We observed a larger plaque size, increased infiltration of T cells and macrophages, a higher collagen content and lower expression of smooth muscle cell (SMC) α-actin in mice treated with recombinant mouse IL-22 (rIL-22) compared to those treated with PBS
Summary
Atherosclerosis (AS) is a highly complex and multifactorial disease, with current data showing that atherosclerosis is the leading cause of death among all human diseases. A growing body of evidence suggests that atherosclerosis is a chronic inflammatory disease that is closely related to innate and acquired immunity.[1,2] During each stage of the disease, progressive atherosclerotic lesions display T-lymphocyte infiltration These T cells interact with local macrophages and vascular smooth muscle cells (SMCs) and affect the expression of inflammatory factors. Total RNA was extracted from the aortas and cells with TRIzol reagent (Invitrogen) according to the manufacturer's instructions for analysis of the IL-22, IL-22R1, CD80, CD86 and IL-17 mRNA levels. We showed that IL-22R1 is expressed in mouse atherosclerotic plaques, and the expression levels of this molecule were similar among groups with varying degrees of atherosclerotic lesions (Figure 3A,B). The aortic plaque burden was substantially greater in the mice treated with rIL-22 than in those treated
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