IL-9: a new culprit in atherosclerosis?

Atherosclerosis is a chronic inflammatory disease of the arterial wall driven by innate and adaptive immunity. Atherosclerotic lesions contain a variety of cells including smooth muscle cells, macrophages, and T lymphocytes, as well as other inflammatory cells, such as mast cells and NKT cells. This collection of cells promotes the development of atherosclerosis through the production of inflammatory factors. Among CD4+T cells, Th 1 cells have been shown to exert proatherogenic effects, whereas regulatory T cells (Treg) display atheroprotective properties and the role of Th2 and Th17 cells remains unclear. The differentiation of Th cells into effector subsets that secrete specific proor anti-inflammatory cytokines is critical for the initiation and progression of atherosclerosis. The development of Th subpopulations is dependent on the expression of lineage-specific transcription factors that are regulated by specific cell–cell interactions, as well as by the cytokine environment. Among these is the recently described Th9 cell subset that preferentially secretes IL-9. IL-9 is a pleiotropic cytokine that is highly expressed in diseases where Th2 cytokines, including IL-4, IL-5, and IL-13, are up-regulated, which explains why it was initially considered as a Th2 cytokine. In addition to Th9 or Th2 cells, mast cells, eosinophils, innate lymphoid cells (ILCs), and NKT cells have been shown to be sources for this cytokine. The differentiation of Th9 cells is dependent on transcription factors that include PU.1, downstream of transforming growth factor-b (TGF-b) signals, and IL-4-activated signal transducer and activator of transcription (STAT)-6 that promotes the expression of interferon regulatory transcription factor (IRF)-4. Other factors suchas IL-1bor IL-2havebeen shown to play important roles for inducing IL-9 production in other cell types aside from Th9 such as, respectively, Th17 and ILC. Th9 cells also produce IL-21, and the secretion of both IL-9 and IL-21 is enhanced by IL-1b that activates STAT1 and promotes subsequent expression of IRF-1. Moreover, the engagement of OX40, a member of the tumour necrosis factor (TNF) receptor superfamily, by its ligand OX40L, expressed on antigen-presenting cells, is a powerful inducer of Th9 cells. The OX40-induced Th9 cell differentiation is involved in airway inflammation in vivo. Interestingly, previous studies have shown the importance of the OX40/OX40L pathway in atherosclerotic development. Th9 cells, and more generally IL-9, have been described as having proinflammatory properties. The majority of cells, such as Th17, ILC, and mast cells, which produce IL-9, also express IL-9 receptor (Figure 1), suggesting autocrine loop effects. IL-9 was initially shown to have proliferative effects on T cells, and thereafter on other cell types, including mast cells, through activation of the Janus kinase (JAK)-STAT pathway. By using IL-9-deficient mice, the importance of IL-9 was shown in pulmonary mastocytosis and goblet cell hyperplasia. Moreover, IL-9 blockade revealed the pathogenic role of IL-9 as a Th17-derived cytokine that regulates IL-6–producing macrophages in the CNS, as well as mast cell numbers in the regional lymph nodes in a mouse model of multiple sclerosis. Also, overexpression of IL-9 transgene in lungs caused an inflammatory response associated with the expression of Th2 cytokines, responsible for the infiltration of inflammatory cells in a murine model of asthma. Accordingly, through these actions, IL-9 appears to be a pleiotropic cytokine that plays pathogenic roles in a broad range of diseases, including asthma, allergy, and autoimmune diseases, making this cytokine an interesting therapeutic target for new drug development. In the context of cardiovascular disease, it is noteworthy that previous studies reported increased IL-9 plasma levels in patients with acute coronary syndrome, as well as in patients with coronary and carotid atherosclerosis. However, the direct implication of IL-9 and Th9 cells in atherosclerosis had not yet been studied. Zhang et al. report for the first time that IL-9 plays a significant role in atherosclerosis. They showed that anti-IL-9 antibody treatment in Apoe mice decreased T-cell and macrophage infiltration within atherosclerotic lesions, and limited the development of atherosclerosis. Conversely, administration of recombinant IL-9 increased inflammatory cell infiltration and plaque size, indicating that IL-9 exerts proatherogenic effects. In the future, it would be of great interest to use IL-9 or IL-9 receptor-deficient mice on either an Apoe or Ldlr background as a continuation of these interesting findings on the involvement of IL-9 in atherosclerosis. This would be particularly interesting since Zhang et al. found no significant differences in IL-9 mRNA between small and large atherosclerotic lesions, nor between Apoe mice on chow or high fat diet, which indicates that IL-9 was not necessarily up-regulated in atherosclerotic mice. To identify the precise mechanisms whereby IL-9 aggravates atherosclerosis, it would also be important to more carefully characterize the cells that produce IL-9 in hypercholesterolaemic mice. In the present study, the majority of IL-9 produced by splenocytes did not originate from