Elsevier

Cytokine

Volume 122, October 2019, 154089
Cytokine

Interleukin 17A in atherosclerosis – Regulation and pathophysiologic effector function

https://doi.org/10.1016/j.cyto.2017.06.016Get rights and content

Highlights

  • IL-17A is elevated in atherosclerotic mouse models and humans with atherosclerosis.

  • Multiple proatherogenic mediators also increase IL-17A expression.

  • IL-17A can act on resident vascular cells and infiltrating leukocytes.

  • IL-17A's mechanistic role in atherosclerosis is modulated by the environment.

  • IL-17A inhibition in patients has not yet shown cardiovascular side effects.

Abstract

This review summarizes the current data on the interleukin (IL)-17A pathway in experimental atherosclerosis and clinical data.

IL-17A is a prominent cytokine for early T cell response produced by both innate and adaptive leukocytes. In atherosclerosis, increased total IL-17A levels and expression in CD4+ T helper and γδ T cells have been demonstrated. Cytokines including IL-6 and TGFβ that increase IL-17A expression are elevated. Many other factors such as lipids, glucose and sodium chloride concentrations as well as vitamins and arylhydrocarbon receptor agonists that promote IL-17A expression are closely associated with cardiovascular risk in the human population. In acute inflammation models, IL-17A mediates innate leukocyte recruitment of both neutrophils and monocytes. In atherosclerosis, IL-17A increased aortic macrophage and T cell infiltration in most models. Secondary recruitment effects via the endothelium and according to recent data also pericytes have been demonstrated. IL-17 receptor A is highly expressed on monocytes and direct effects have been reported as well. Beyond leukocyte accumulation, IL-17A may affect other factors of plaque formation such as endothelial function, and according to some reports, fibrous cap formation and vascular relaxation with an increase in blood pressure. Anti-IL-17A agents are now available for clinical use. Cardiovascular side effect profiles are benign at this point.

IL-17A appears to be a differential regulator of atherosclerosis and its effects in mouse models suggest that its modulation may have contradictory effects on plaque size and possibly stability in different patient populations.

Introduction

The pro-inflammatory cytokine interleukin (IL)-17A has received major immunologic attention in the last years as a marker of a novel T helper cell lineage, TH17 cells. Its regulation and physiologic functions have been explored in a variety of disease models and its concentrations associated with human pathologies. By now, there is a sizeable number of murine and human studies investigating its role in atherosclerosis [1], [2], [3], [4]. This review aims to summarize the current knowledge of factors that promote IL-17A expression in pro-atherogenic conditions and the available data on its role in plaque development and structure. Finally, cardiovascular data from current trials of IL-17A antagonists in humans provide an outlook to possible clinical applications.

Section snippets

The IL-17 cytokine family, regulation, producing cell types and receptors

The IL-17 family consists of six members in total, termed IL-17A to F, which signal through five heteromeric receptor subunits, termed A to E [5]. IL-17A is the best-investigated cytokine of this family and the topic of this review. However, there are reports of IL-17F regulation in hypertension and vascular injury [6], [7]. This is interesting as IL-17F is the closest genetic and functional homologue of IL-17A and signals through the same main receptor unit, IL-17 receptor A (gene name:

Regulation of IL-17A production during atherosclerosis development in murine models

IL-17A is mainly produced by T helper cells that are termed TH17 according to this signature cytokine. Depending on health status and location, other cell types, most notably γδT cells and innate lymphocytes produce significant amounts of IL-17A as summarized elsewhere [2], [5], [14]. Production by other cells such as monocytic cells and neutrophils is controversial [15], [16], [17]. IL-17A measurements during atherosclerosis development are summarized in Table 1. IL-17A was elevated in Apoe−/−

Cytokines

Polarization to TH17 cells in mice is induced by combined action of transforming growth factor beta (TGFβ), IL-6 and IL-23, the latter being central for stabilization of the cell type and these relationships have been reviewed [21], [22], [23], [24], [25]. Among other cytokines that can further promote TH17 cells are IL-1, especially in human cells, and GM-CSF [26], [27], [28]. The TH17 defining transcription factors STAT3 and RORγt promote TH17 signature cytokines in response to these stimuli

Hypertension

Immune mediators of hypertension and related end-organ damage including atherosclerosis include the IL-17A response [66], [67]. In a number of small cohort studies, IL-17A serum levels were associated with refractory hypertension [68], [69]. Inflammation-induced hypertension was promoted by IL-17A in a mouse model [70]. Angiotensin II, that is also a prominent hypertensive agent, induces IL-17A production in a variety of inflammatory conditions in vivo [71], [72] and can enhance TH17

Genetic IL-17A and IL-17 receptor A deletion

A commonly used animal model for mechanistic atherosclerosis studies are Apoe−/− mice. Lesion formation is mainly driven by excessive blood lipid levels, both with normal “chow” and high fat “western type” diet. Lesion sizes in studies with in Il17a−/−Apoe−/− mice in the aortic root and the whole aorta are summarized in Table 2. Results range from ameliorated [59], [104], unchanged [6] to increased lesion size [105] compared to control mice. Most of these studies were conducted on a high fat

Role of IL-17A in modulation of the atherosclerotic lesion structure

For the clinical outcome of atherosclerosis not only the size of the plaque is important but also factors that influence the structure, stability or inflammatory state. Unstable plaques are prone to rupture, leading to thrombosis and cardiovascular events including death [32], [121]. Plaque instability is promoted by factors like decreased collagen deposition, increased matrix degradation by metalloproteinases, or imbalanced clearance of apoptotic cells. Deficiency of IL-17A had controversial

Possible IL-17A target cells in atherosclerosis

Inflammatory leukocytes are central in plaque development [32]. IL-17A and its main receptor subunit, IL-17 receptor A, regulate myeloid cells including granulocytic and monocytic response in infection and sterile inflammation [26]. Both, direct effects on myeloid leukocyte functions and actions via resident cell types in the vasculature have been reported [124].

In LDLr−/− mice, IL-17 receptor A deficient bone marrow significantly reduced IL-6 levels and aortic root lesion size, indicating an

Role of IL-17A in human atherosclerotic plaque structure

Immunohistological staining for IL-17A in human atherosclerotic plaques has been reported by a number of groups. While most detected an increase in unstable plaques [135], [136], [137], [138], IL-17A according to immunohistochemisty and western blot was associated with fibrotic rather than macrophage rich plaque areas in another study [112]. Also, mRNA expression of the TH17 defining transcription factor RORγt was associated with pro-fibrotic gene expression in human endarterectomy specimens

Effects of specific IL-17A antagonists on human atherosclerosis

Direct IL-17A blockade has now been used in a number of clinical trials, mostly psoriasis and inflammatory bowel disease [80]. There was no significant change in cardiovascular risk in recent metaanalyses for either psoriasis [150] or Crohn’s disease [151]. Also for IL-23 antagonists, which appear to be more effective in psoriasis [80], meta-analyses did not detect a significantly altered rate of major adverse cardiovascular events [1], [150], [152]. However, effects in a broader population

Conclusion

A large body of work conclusively shows IL-17A up-regulation in atherosclerosis. Its pathophysiologic role according to the majority of mechanistic studies in mouse models appears to be an increase in plaque size and aggravation of inflammation. However, there are contradictory findings. Possible reasons for this are different levels of inflammation and T cell polarization in the used mouse models. IL-17A actions on both leukocytes and resident vascular cells that may modulate plaque structure

Disclosure

The authors have no competing financial interests regarding this work.

Acknowledgements

S.v.V. was supported by Deutsche Forschungsgemeinschaft and Else Kröner Fresenius Stiftung.

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