Stressed hearts inflame the body (in a good way)

Heart failure is a global health problem, with an estimated 30–50 million patients diagnosed worldwide (1, 2). Therapeutic advances have reduced early mortality; however, morbidity caused by damaged or failing ventricles remains high. Indeed, heart failure is the most common cause for hospitalization in elderly individuals, with recalcitrant 5-y survival rates remaining worse than most cancers (2). Sustained stress from abnormal mechanical load, neurohormone stimulation, and genetic defects are all potent inducers of heart failure (3, 4). These trigger conversations among vascular, muscle, and inflammatory cells, as well as fibroblasts using a myokine/cytokine vocabulary that can be shared by the multiple cell types or be more specific. As recently reviewed by Ghigo et al. (5), growing evidence has positioned the myocyte as a “Master and Commander” for coordinating interstitial responses to myocardial stress, including fibrosis, vascular remodeling, and inflammation. In hearts subjected to pressure overload, myocyte secretion of interleukins (IL-1β, -6, -18), TNF-α, receptor activator of NF-κB ligand, and macrophage chemoattractant protein-1 all signal to inflammatory responses, whereas ischemic disease engages additional factors, such as the adhesion molecules ICAM-1 and VCAM-1, and anti-inflammatory growth differentiation factor 15 (5). Depending on the stress, this coordinated inflammatory conversation can impact myocyte growth and survival, as well as remove damaged or dead cells.

IL-33 is a member of the IL-1 superfamily and promotes inflammation in parasitic infection, bronchial asthma, rheumatoid arthritis, and sepsis (6, 7). ST2 was identified as an orphan receptor among the IL-1 receptor family and now it is known as IL-33 receptor (7). Soluble ST2 (sST2) lacks the transmembrane domain of ST2, and serves as a decoy receptor reducing IL-33 signaling (7). Intriguingly, IL-33/ST2 signaling inhibits pathological remodeling in the myocardium by NF-κB, extracellular response kinase (ERK), and activator protein 1 (AP-1) signaling pathways, although exact mechanisms remain unclear. Sanada et al. (8) first reported that IL-33/ST2 signaling protects against pressure overload-induced left ventricular dysfunction and hypertrophic/fibrotic changes. Subsequent studies showed sST2 is a biomarker for prognosis in patients after myocardial infarction (9) and heart failure (10, 11), with high levels independently correlating with mortality. In PNAS, Chen et al. (12) used cell-targeted gene modifiers to disrupt the IL-33/ST2 local conversation in pressure-overloaded myocardium, revealing how myocyte ST2 and endothelial-derived IL-33, play a critical role in the cardiac hypertrophic and systemic inflammatory responses (Fig. 1).

Fig. 1.

Proposed mechanism of IL-33/ST2-mediated protection in stressed hearts. Endothelial cells activated by pressure overload produce IL-33, which then stimulates myocyte ST2 receptors. Cardiac fibroblasts also produce IL-33. From earlier studies, ST2 signaling is thought to attenuate left ventricular hypertrophy by inhibiting NF-κB, ERK-1, and AP-1 signaling. sST2, a decoy receptor of ST2, blocks IL-33 binding to ST2 and blunts its signaling via autocrine or paracrine mechanisms. Secreted IL-33 enters the bloodstream and induces selective systemic inflammation involving IL-13 and TGF-β1, both of which being protective in some cardiovascular pathological processes.

Using gain- or loss-of-function strategies by injecting adenovirus encoding ST2L (transmembrane receptor) or sST2 in normal mice or animals lacking ST2, Chen et al. (12) show selective myocyte targeting of this signal is protective or detrimental, respectively, when the heart is confronted with pressure overload. This gene delivery method leads to a mosaic of cell-to-cell expression, and this revealed antihypertrophic effects were confined either to the gene-modified cell itself, or in the case of sST2, also to the one right next to it, but no further. Thus, ST2L and sST2 regulation is very local. Next, Chen et al. created conditional mutant mice lacking IL-33 or ST2 gene expression exclusively in cardiomyocytes or endothelial cells. Pressure overload hypertrophy was worse in myocyte but not endothelial-specific ST2-deficient mice, whereas the opposite held for IL-33 knockdown, where only endothelial-targeted deletion worsened hypertrophy. Immunofluorescence revealed both fibroblast and endothelial IL-33 expression were enhanced after pressure overload, the former peaking on day 3; the latter rose later. These studies also revealed a reciprocal rise in sST2 with suppression of endothelial IL-33, suggesting IL-33 normally enhances ST2 signaling in the myocardium to blunt hypertrophy. Chen et al.’s next observation was particularly intriguing, as they showed endothelial IL-33 triggered by myocardial pressure-overload stress generates a systemic inflammatory signal. This was selective, as cardiac and systemic blood levels of proinflammatory mediators, such as IL-1β, IL-6, and TNF-α were unaltered, whereas IL-13 and TGF-β1 rose when endothelial IL-33 increased. The latter was interpreted as protective rather than harmful, and although IL-13 is protective in myocardial infarction by induction of regulatory macrophage differentiation and promotion of wound healing (13), its role in pressure overload is uncertain. TGF-β1 signaling can exacerbate both cardiac hypertrophy and fibrosis (14). In this regard, only chamber and myocyte hypertrophy were reported, and other potential changes, such as inflammation, fibrosis, and cardiac dysfunction were not. Thus, whether endothelial IL-33–coupled systemic inflammatory activation is all good remains speculative.

In hypertension, damage-associated molecular patterns (DAMPs) and neo-antigens formed by vascular injury trigger innate immunity mediated by macrophages and natural killer cells. DAMPS and neo-antigens induce proinflammatory T-lymphocyte subsets Th1/Th17, which lead to maintenance of hypertension and end-organ damage through IFN-γ, IL-2, IL-17, and reactive oxygen species. Regulatory T cells counteract hypertension and tissue injury via IL-10 and TGF-β (15, 16). Chen et al.’s (12) study adds endothelial-derived IL-33 to this signaling vocabulary. Although the gene-knockdown strategy could not prove that IL-33 came only from cardiac endothelial cells, the locally constrained ST2 signaling suggests a prominent local effect in the heart. This might result from mechanical load linked to greater myocardial contractile stress or intravascular flow/distension forces, but might also be a result of systemic endothelial activation by other released cytokines.

Chen et al.’s (12) study also finds a potentially important time-course disparity between when IL-33 gene expression was largely from fibroblasts (peaking on day 3 after pressure overload) versus endothelial cells (days 7–14). Prior work by the same

The Chen et al. study further reveals how personal communications between myocytes and their immediate neighbors can impact remodeling and systemic signaling.

group suggested cardioprotective IL-33/ST2 signaling is mediated by fibroblast-derived IL-33 (8), and whereas the current data certainly shows a critical role for endothelial-derived IL-33 at a later stage, the prior impact from fibroblasts may be important as well. The systemic cytokine analysis provides data only at day 7, and whether the earlier time point would indeed reveal no changes from endothelial cell-derived IL-33 deletion (e.g., fibroblasts are dominant then), is unknown. Myocardial inflammatory infiltration occurs early after transverse aortic constriction (around day 3) (17), so critical signaling likely occurs before a role of endothelial IL-33.

Chen et al. (12) have added potent evidence that targeted cell-selective conversations in the wall of the heart not only regulate local cardiac stress responses, but also trigger more disseminated signaling via secreted factors. Other recent examples are differential responses to TGF-β receptor signaling depending upon which cell type does the talking. In response to both pressure overload and myocardial infarction, hearts with myocytes selectively lacking the TGF-β-R2 receptor are protected, whereas blocking this signaling in interstitial cells alone is not or makes it worse (18, 19). With ischemic disease, the mechanism also appears to involve enhanced myocyte-directed signaling that results in more IL-33, GDF15, and other protective cytokine release. The Chen et al. (12) study further reveals how personal communications between myocytes and their immediate neighbors can impact remodeling and systemic signaling.