Blocking Interleukin-1β transiently limits left ventricular dilation and modulates cardiac lymphangiogenesis in a mouse pressure-overload model

Abstract

Blocking inflammatory pathways, such as the inflammasome or IL-1β, is a promising therapeutic target in both ischemic and non-ischemic heart failure (HF). We hypothesize that IL-1β may stimulate cardiac lymphangiogenesis, driven by left ventricular dilation in HF. Thus, blocking IL-1β signaling may reduce lymphangiogenesis, which could delay resolution of myocardial edema and inflammation, aggravate cardiac fibrosis, and accelerate HF development. Here, we investigated the effects of early versus late anti-IL-1β treatment during pressure-overload induced by transaortic constriction (TAC) in Balb/c mice prone to left ventricular (LV) dilation. We also investigated links between perivascular lymphatics and fibrosis in ischemic versus dilated cardiomyopathy (DCM) HF patients. We found that early treatment transiently delayed LV dilation, but did not alter cardiac hypertrophy or dysfunction at 8 weeks post-TAC. Late treatment reduced cardiac lymphangiogenesis and lymphatic CCL21 gradients. Surprisingly, cardiac inflammation, fibrosis and dysfunction were not aggravated despite reduced lymphatic density. Further, similar as in mice, increased perivascular lymphatic density in HF patients was associated with less perivascular fibrosis. In conclusion, we found limited functional cardiac benefit of IL-1β blockage when initiated before onset of lymphangiogenesis post-TAC in Balb/c mice. In contrast, late treatment reduced cardiac lymphangiogenesis. HF onset was however not significantly accelerated, likely reflecting lymphatic transport dysfunction post-TAC. Taken together, the therapeutic window for anti-IL-1β treatment appears crucial, as initiation of treatment during the lymphangiogenic response, induced by LV dilation, may limit the potential cardiac benefit in HF patients. Further, our data indicate that IL-1β-independent perivascular lymphangiogenesis may limit perivascular fibrosis.