IL-17 in atherosclerosis: the good and the bad

This editorial refers to the article ‘Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content’ by S. Brauner et al., pp. 158–167. The rupture of atherosclerotic unstable plaques may cause stroke or myocardial infarction. Immune cells, including T helper (h)1 lymphocytes, are major players in the initiation and progression of atherosclerosis.1 Th17 cells have also been shown to be involved in atherosclerosis, even though their role remains controversial.2 The contradictory findings might be accounted for by the mouse model and the experimental strategy used, but also by the potential pathogenic or protective effects of Th17 cells, which depend on the different environmental cues. Th17 cells are considered as inducers of inflammation that could protect against pathogen invasion. However, at the same time, they have a dark side, as these cells are important drivers of autoimmune and inflammatory diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis.3,4 Th17 cells can produce factors such as interleukin (IL)-6, interferon (IFN)-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which contribute to their pathogenicity.5,6 Pathogenic Th17 cells can also result from the conversion of other cell types, such as T regulatory (Treg) cells, which lose the expression of the specific regulatory T-cell transcriptional factor, forkhead box P3 (Foxp3) during their differentiation towards the Th17 lineage.7 One of the key inducers of pathogenic Th17 cells is the cytokine IL-23. In fact, the absence of IL-23 prevents the acquisition of IFN-γ and GM-CSF production by Th17 cells.8 Other factors such as IL-1β and transforming growth factor (TGF)-β3 have been reported to also give rise to pathogenic Th17.9 On the other hand, it is becoming clear that these cells have also a key non-pathogenic role, particularly in the intestine, in the defense against opportunistic pathogens of fungal or bacterial origin.10 Intestinal Th17 cells can transdifferentiate into protective IL-10-producing cells, which depends on TGF-β1 signaling.11 These Th17 dichotomy and function plasticity in response to diverse range of environmental signals may have important roles in determining the role of Th17 cells in inflammatory diseases and particularly in atherosclerosis. In this current issue of Cardiovascular Research, Brauner et al.12 report the effects of Tri-partite motif (TRIM) 21 deletion in chimeric low density lipoprotein receptor (Ldlr−/−) mouse model. They showed that in absence of TRIM21 in bone marrow, the mice have elevated Th17 cells in plaques, lower matrix metalloproteinase (MMP) 9 level in the aorta and developed larger fibrotic plaques with higher collagen content.12 Interestingly, TRIM21 expression negatively correlates with Th17-associated genes (IL-23 and GM-CSF) and collagen type 1 content in human carotid plaques.12 Moreover, the expression of MMP1, MMP8, MMP9 was significantly higher in human plaques with high TRIM21 expression, as compared with those with low TRIM21 expression.12 Collagen plays a key role in determining plaque stability.1 The mechanisms leading to such increase of collagen could result from a decrease of MMP expression, which may account for lower matrix degradation and/or the increase of synthetic smooth muscle cells (SMC), as assessed by higher expression of osteopontin in the aorta of Ldlr−/− mice reconstituted with TRIM21-deficient bone marrow compared to controls.12 However, whether these effects could result from either TRIM21-direct effects or indirect IL-17-dependent mechanisms remain an open question. Therefore, it would be interesting to examine, in this model, plaque composition following in vivo neutralization of the IL-17 pathway. The increased propensity toward Th17 differentiation in absence of TRIM21 seems specific, as no change of IL-4 (Th2) or IFN-γ (Th1) was observed.12 Most likely, the observed findings were due to increased IL-17 production in absence of TRIM21. In a previous publication, the same group showed that IL-17 is able to induce collagen synthesis by SMC.13 Furthermore, IL-17 expression was shown to be positively associated with the SMC marker ACTA2 (encoding α-SM-actin) and with collagen 1 mRNA in human carotid plaques,13 supporting the notion that IL-17 favors plaque stability by promoting fibrous cap formation, in agreement with our previous study showing that IL-17 expression in human carotid plaques was associated with a lower macrophage but higher SMC content, and a stable fibrous plaque phenotype.14 These results are at odds with others showing that IL-17, instead, induced SMC inflammation and apoptosis.15,16 However, these effects were observed in association with other inflammatory factors such TNF-α and IFN-γ.15,16 TRIM21 is an ubiquitin E3 ligase that has been involved in tissue inflammation and systemic autoimmunity.17 In the present study, the authors did not investigate for the mechanisms explaining how TRIM21 regulates IL-17 expression. A previous study showed that TRIM21 controls interferon regulating factors (IRF) and NF-κB cascades leading to down-regulation of inflammatory factors such as IL-6, TNF-α, IFN-α, IFN-β, and IL-12/IL-23.17 Moreover, invalidation of TRIM21 led to inflammation and autoimmunity, which were dependent on the IL-23-inducing IL-17 cytokine,17 suggesting the induction of the pathogenic Th17 pathway. Conversely, herein, invalidation of TRIM21 in a murine model of atherosclerosis induced higher IL-17 that was produced in an anti-inflammatory context, as assessed by in vitro transcriptomic analysis of Th17 cells, showing increased expression of genes regulated by TGF-β1, suggesting the induction of a non-pathogenic Th17 pathway. It would be interesting to investigate the molecular mechanisms leading to such divergence in disease outcome. IL-17 neutralizing strategy using anti-IL-17 monoclonal antibody are promising therapeutic approach to treat psoriasis and arthritis. However, specific attention is needed as clinical trials evaluating the use of such antibodies reported increased adverse cardiovascular events, such as stroke and myocardial infarction in the treated groups, even though statistical difference was not significant.18 The gut microbiota is now considered as a novel contributor to the development and progression of atherosclerosis.19 The intestine is the home of diverse bacteria and cytokine-producing cells, and their interplay have been increasingly recognized to affect immune homeostasis. Among these cytokines, IL-17 is highly expressed in the gut tract, even at steady state, which may impact disease development.10 Further investigation of the manner in which microbiota-regulated Th17 may affect atherosclerosis development represents a promising area of investigation to better understand organ interplay in the context of inflammatory disease. In conclusion, the present findings by Brauner et al.12 provide strong evidence for a role of TRIM21/IL-17 in controlling plaque stability (Figure 1), which supports the notion of non-pathogenic Th17 pathway in atherosclerosis. Potential effects of IL-17 in atherosclerosis. Tri-partite motif (Trim)21 is an important negative regulator of interferon regulatory factor (IRF)-dependent IL-23 production. Invalidation of Trim21 stimulates IL23 production, which contributes to the formation and maintenance of Th17 cells. Increased IL-17 production is associated with an increase of synthetic SMC which may result from an increase of their proliferation or a decrease of cell apoptosis, as well as higher collagen synthesis and lower expression of some MMPs. These features characterize stable fibrotic plaque. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.