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IL-17 in atherosclerosis: the good and the bad.

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. Th17 cells have also been shown to be involved in atherosclerosis, even though their role remains controversial. 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. Th17 cells can produce factors such as interleukin (IL)-6, interferon (IFN)-c, and granulocyte-macrophage colony-stimulating factor (GMCSF), which contribute to their pathogenicity. 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. 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-c and GM-CSF production by Th17 cells. Other factors such as IL-1b and transforming growth factor (TGF)-b3 have been reported to also give rise to pathogenic Th17. On the other hand, it is becoming clear that these cells have also a key nonpathogenic role, particularly in the intestine, in the defense against opportunistic pathogens of fungal or bacterial origin. Intestinal Th17 cells can transdifferentiate into protective IL-10-producing cells, which depends on TGF-b1 signaling. 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. 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. Interestingly, TRIM21 expression negatively correlates with Th17associated genes (IL-23 and GM-CSF) and collagen type 1 content in human carotid plaques. 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. Collagen plays a key role in determining plaque stability. 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. 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-c (Th1) was observed. Most likely, the observed findings were due to increased IL17 production in absence of TRIM21. In a previous publication, the same group showed that IL-17 is able to induce collagen synthesis by SMC. Furthermore, IL-17 expression was shown to be positively associated with the SMC marker ACTA2 (encoding a-SM-actin) and with collagen 1 mRNA in human carotid plaques, 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. These results are at odds with others showing that IL-17, instead, induced SMC inflammation and apoptosis. However, these effects were observed in association with other inflammatory factors such TNF-a and IFN-c. TRIM21 is an ubiquitin E3 ligase that has been involved in tissue inflammation and systemic autoimmunity. 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-jB cascades leading to downregulation of inflammatory factors such as IL-6, TNF-a, IFN-a, IFN-b, and IL-12/IL-23. Moreover, invalidation of TRIM21 led to inflammation and autoimmunity, which were dependent on the IL-23-inducing IL-17 cytokine, 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,