Interleukin 17A in atherosclerosis – Regulation and pathophysiologic effector function
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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2021, NefrologiaCitation Excerpt :IL-17A is produced by cells other than Th17, including γδ lymphocytes (Fig. 1), and probably also by neutrophils, invariant natural killer T cells, CD8 + cells, innate lymphoid cells, and mast cells, although in some Of these cells, there is controversy as to whether they are only capable of storing IL-17A but not producing it, as could be the case with mast cells.30,37,47,48 IL-17A generates pro-inflammatory responses that can vary substantially depending on the cell type and pathological conditions.9,10,11,13,49–54 One of the first evidences of the involvement of IL-17A in the inflammatory response showed that in cultured synoviocytes from patients with rheumatoid arthritis, IL-17A increased the levels of IL-6 and IL-8.54
IL17RA in early-onset coronary artery disease: Total leukocyte transcript analysis and promoter polymorphism (rs4819554) association
2020, CytokineCitation Excerpt :Th17 are a group of CD4 + cells that would regulate the progression of atherosclerosis [5]. This cells secrete cytokines of the Il-17 family, that animal studies have shown to be important for the origin, progression, stability and rupture of the atherosclerotic lesion [6–8]. The inhibition of il-17a in mice reduced the vascular inflammatory burden and cellular infiltration, and prevented the progression of the atherosclerotic lesion improving the lesion stability [6].
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2019, CytokineCitation Excerpt :Confusingly, reconstitution of LDLr−/− mice with IL-17A deficient bone marrow did not alter lesion size, despite the significant reduction in serum IL-17A levels [95], while reconstitution with IL-17A receptor deficient bone marrow in LDLr−/− mice reduced lesion development [98]. This indicates the complexity of IL-17 and that of Th17 cells in atherosclerosis, as was also recently reviewed [70]. Further studies are required to determine the exact contribution of IL-17 to the development and progression of atherosclerosis, and how IL-23 may affect the Th17 cell population.