心の健康におけるIL-1βの役割

タイトル: Blocking Interleukin-1beta transiently limits left ventricular dilation and reduces cardiac lymphangiogenesis in a mouse pressure-overload model

概要: Blocking inflammatory pathways, e.g. the inflammasome or interleukin (IL)-1{beta}, is a promising therapeutic approach in heart failure (HF). We hypothesized that IL-1{beta} may stimulate cardiac lymphangiogenesis in response to left ventricular (LV) dilation following pressure-overload. Consequently, blocking IL-1{beta} may reduce lymphangiogenesis, delaying resolution of myocardial edema and inflammation, aggravating cardiac fibrosis, and accelerating HF development. Here we investigated the effects of anti-IL-1{beta} treatment during HF development following pressure-overload, induced by transaortic constriction (TAC) in BALB/c mice prone to LV dilation. We examined the molecular mechanisms of IL-1{beta} in macrophages and lymphatic endothelial cells, and assessed links between perivascular fibrosis and lymphatics in HF patients with ischemic or dilated cardiomyopathy (DCM). We found that early anti-IL-1{beta} treatment transiently delayed LV dilation, but did not alter cardiac lymphangiogenesis, hypertrophy, or dysfunction at 8 weeks post-TAC. In contrast, late anti-IL-1{beta} treatment reduced cardiac lymphangiogenesis in response to LV dilation. This was linked to a cell non-autonomous role of IL-1{beta} in promoting cardiac lymphangiogenesis through stimulation of macrophage production and maturation of VEGF-C. Surprisingly, despite reduced lymphatic density in late anti-IL-1{beta}-treated mice, cardiac inflammation, interstitial fibrosis, and dysfunction were not aggravated. Further, we found that perivascular lymphatic density, unaltered by IL-1{beta}, was negatively associated with perivascular fibrosis in HF patients and our TAC model. In conclusion, IL-1{beta} blockage elicited transient functional cardiac benefit when initiated before onset of LV dilation post-TAC in mice. In contrast, late treatment reduced cardiac lymphangiogenesis, but did not significantly accelerate HF development, likely reflecting lymphatic transport dysfunction post-TAC. Our data suggest that the therapeutic window for anti-IL-1{beta} treatment is crucial, as initiation of treatment during the lymphangiogenic response, induced by LV dilation, may diminish the potential cardiac benefit in HF patients. Finally, our data indicate that IL-1{beta}-independent perivascular lymphangiogenesis may limit perivascular fibrosis.