More on CCL17 as a Target to Reduce Inflammation in Cardiovascular Disease
Atherosclerosis is the buildup of fatty plaques in the walls of blood vessels, impeding blood flow and eventually rupturing to produce a heart attack or stroke. It is the single largest cause of human mortality. Atherosclerosis is in part an inflammatory condition, accelerated by the state of chronic inflammation that arises in later life. In this context, levels of CCL17 have been shown to rise with age, while inhibition of CCL17 has been shown to reduce chronic inflammation and slow the progression of atherosclerosis. This outcome is achieved via effects on T cell behavior; CCL17 is expressed on the surface of dendritic cells and interacts with CCR4 on the surface of T cells. In doing so it represses the anti-inflammatory activity of regulatory T cells.
Researchers continue to investigate the biochemistry involved in this relationship. The authors of today's open access paper here report that CCR4 isn't the only receptor involved, and CCL17 also binds to CCR8. This sort of investigative work is necessary to understand how and where to target a specific mechanism. As researchers note, CCL17 does have a normal, useful role in coordinating transient immune activity where it is needed. As is the case for most age-related dysregulation of immune function, one can't just inhibit an overactive mechanism without consequences, as excessive immune activate uses the same pathways as normal immune activation. The aim of tracing the various interactions involved like this is to find a point of intervention that only affects pathology, rather than also suppressing necessary immune system activity. The results reported here are likely only one step of many needed to reach that goal, if it can be attained.
New signaling pathway uncovered, shedding fresh light on atherosclerosis
A chronic inflammatory disease of the inner walls of blood vessels, atherosclerosis is responsible for many cardiovascular conditions. Dendritic cells, which act to recognize foreign substances in the body and mount an immune response, play an important role in the disease. They produce the signaling protein CCL17, a chemokine, which influences the activity and mobility of T cells, which track down infected cells in the body and attack the pathogens. However, CCL17 can also promote cardiovascular pathologies. People who suffer from cardiovascular diseases, or are particular susceptible to such diseases, have elevated levels of the signaling protein. In humans and mice, elevated CCL17 serum levels are associated with increased risk of atherosclerosis and inflammatory diseases of the cardiovascular and digestive systems.
"We know from our previous work that a genetic deficiency or an antibody blockade of CCL17 impedes the progress of atherosclerosis." Before now, only one signal receptor was known to contribute to the recruitment and functions of T cells. If this receptor is lacking, however, the body is not protected from the negative effects of CCL17. Mice that did not possess the receptor in question continued to have the same extent of disease driven by CCL17. If the signaling protein acted directly and exclusively on this receptor, then silencing it should have the same effects as the absence of CCL17. Consequently, there must be another signaling pathway in which CCL17 is involved, and the researchers demonstrated and described just such a pathway in the course of the new study. "We furnish clear evidence that CCL17 acts through an alternative receptor with high affinity, thereby triggering a signaling pathway that results in the suppression of anti-inflammatory, so-called regulatory T cells."
CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4.
Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, whereas FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Treg cells.