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). Using gainor 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.