ST2 and Functional Ligands — Interleukin-33 and IL-33/ST2 Signalling

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ST2 and Functional Ligands — Interleukin-33 and IL-33/ST2 Signalling

Despite that ST2 was first described in 1989, it was not until 2005 when the IL-33 was identified as its functional ligand.71 Secreted IL-33 mediates its effects in target cells by binding ST2L,^66,71,72 as part of the IL-33 receptor (IL-33R) complex; this is a heterodimeric receptor constituted by the ST2L transmembrane protein, which is the ligand-binding subunit, and by the so-called IL-1 receptor accessory protein (IL-1RAcP), which seems to be necessary for the IL-33-mediated signal transduction and its effects in vivo.^66,72,73 Once IL-33 binds the IL-33R complex, signalling is induced through the TIR domain, leading to the recruitment of different proteins (e.g. myeloid differentiation primary-response protein ⁸⁸ [MyD88], IL-1R-associated kinases [IRAK], tumour necrosis factor [TNF] receptorassociated factor 6 [TRAF-6]) and subsequent activation of different signalling pathways (e.g., transcription nuclear factor-κB [NF-κB] pathway, mitogen-activated protein kinases [MAPK] pathway, PI3K/Akt), which ultimately leads to the production and secretion of different inflammatory factors, chemokines and cytokines.^{67,70,71,73–81}

IL-33 is widely expressed in many tissues, including the heart,^71,74 and in many cells, including, among others, endothelial and smooth muscle cells, cardiomyocytes, fibroblasts or macrophages.^71,74,78,82 A dual role for IL-33 has been described, both as a cytokine released from the cells (cytokine-like, therefore binding ST2L in target cells), and as an intracellular nuclear factor (nuclear factor-like).^74,75,79,83 In fact, IL-33 was first described as a nuclear factor with a DNA-binding domain present in endothelial cells.⁸⁴ A nuclear location of IL-33 has later further confirmed, although the pathophysiological role of IL-33 as a nuclear factor is not well-known;^{78,82,85–88} different studies have suggested that IL-33 could play a role as a danger endogenous signal, which would be released as an active full-length protein to alert cells of immune system during damage or infection, whereas in case of apoptosis IL-33 would be cleaved and inactivated by caspases, preventing an inflammatory response in case of programmed cell death.^{74,75,78,79,82,83,89–93} This would be supported by the wide expression of IL-33 in cell types in normal human tissues,^{71,74,78,79,82,88,89} suggested to be constitutively expressed in the nucleus of several cell types, including human endothelial cells, fibroblasts, cardiomyocytes and coronary artery smooth muscle cells.^78,82,88

Soluble ST2 in the Cardiovascular System

The expression of ST2 in the cardiovascular system was first described by Weinberg et al. in 2002, when the authors observed that serum levels of ST2 and levels of mRNA ST2 in left ventricular (LV) tissue were significantly increased in rat cardiomyocytes subjected to mechanical strain and in an in vivo model of experimental myocardial infarction (MI) in mice by ligation of a coronary artery compared with controls not subjected to these procedures.⁹⁴ These experimental results were also supported in humans after studying 69 patients with acute MI randomly selected from the Healing and Early Afterload Reducing Therapy (HEART) study: serum ST2 levels at day 1 were significantly higher compared with those at days 14 and 90, and correlation studies suggested that ST2 might be related with the extent of myocardial injury or biomechanical load after MI.⁹⁴ Later studies have confirmed and expanded these initial findings, demonstrating a cardioprotective effect of IL-33 through ST2 signalling, in both in vitro and in vivo models.^{67,68,71,76,78,80,86,95} For instance, treatment with IL-33 was found to reduce the infarct volume and fibrosis in rats 15 days after ischaemia-reperfusion injury, as well as to improve echocardiographic and invasive haemodynamic parameters, suggesting that the beneficial structural changes produced by IL-33 may also lead to a better cardiac contractile function.⁶⁸ Sanada et al. confirmed a role of IL-33/ST2 signalling in controlling cardiomyocyte hypertrophy and cardiac fibrosis in vitro (rat neonatal cardiomyocytes and cardiac fibroblasts subjected to biomechanical strain) and in vivo (pressure overload induced by transverse aortic constriction [TAC]);⁶⁷ additionally, administration of sST2 decreased the antihypertrophic effect of IL-33 in a dose-dependent manner, and blocking the ST2L receptor with an anti-ST2L monoclonal antibody also eliminated the effects of IL-33, unlike controls.⁶⁷ These results have been further confirmed in vivo in ST2-null mice, lacking both ST2L and sST2 (ST2-/-) subjected to TAC;^67,68 compared with wild-type mice, ST2-null mice showed increased cardiac fibrosis and hypertrophy, macrophage infiltration, impaired echocardiographic parameters (including impaired systolic function or increased left ventricle dilation), increased gene expression of NP or increased mortality; by treating with IL-33, these findings were reduced and survival improved in wild-type mice but not in ST2-/-.^67,68 Different mechanisms, such as inhibition of cardiomyocyte apoptosis and increased expression of anti-apoptotic proteins, reduced mast cell density in infarct areas, promotion of a shift towards a Th2 response in lymphocytes, involvement of cardiac stem cells influencing processes as regeneration, differentiation or repairing after injury (autocrine or paracrine signalling), inhibition of cardiac fibroblasts migration or activation of different cytokines expression, among others, have been suggested to be involved in the beneficial effects of the IL-33/ST2 pathway.^68,76,78,95

Altogether, data from both in vitro and in vivo models suggest a cardioprotective effect of IL-33 through ST2 signalling: IL-33, mechanically or by injury (ischaemia) induced in both, cardiac fibroblast and cardiomyocytes, and acting as a ligand for the ST2L receptor, would play a favourable cardioprotective role against hypertrophic-, fibrotic- and inflammatory-related signals following mechanical overload or injury; sST2 would act as a decoy receptor that binding IL-33 in blood prevents its action through the ST2L receptor.

An atheroprotective role of IL-33 through ST2L signalling, counteracted by sST2, has also been described,^{69,70,81,96,97} including a reduction in the atherosclerotic lesion size,⁶⁹ lower macrophage foam cell accumulation in the plaques⁹⁷ or promotion of angiogenesis.⁸¹ A modulatory role of IL-33/ ST2L in the inflammation of atherosclerosis has been proposed to explain these effects, such as promoting a Th1-to-Th2 switch response (Th2- mediated immunity),⁶⁹ increased levels of oxidised-low-density lipoprotein (LDL) antibodies,⁶⁹ regulation of adhesion molecules⁷⁰ or an increased activity of T-reg cells.⁹⁶