Pré-Publication, Document De Travail Année : 2023

Blocking Interleukin-1β transiently limits left ventricular dilation and reduces cardiac lymphangiogenesis during pressure-overload in mice

Jb. Michel

Résumé

Blocking pro-inflammatory pathways, e.g. the inflammasome or interleukin (IL)-1β, is a promising therapeutic approach in heart failure (HF). We hypothesized that IL-1β may regulate cardiac lymphangiogenesis in response to chronic pressure-overload, and hence could impact the resolution of myocardial edema and inflammation and the development of cardiac fibrosis and HF. We investigated cardiac, lymphatic, and immune effects of anti-IL-1β treatment during HF development following pressure-overload induced by transaortic constriction (TAC) in BALB/c mice. We also examined the impact of IL-1β on macrophages and lymphatic endothelial cells in vitro , and assessed links between perivascular fibrosis and lymphatics in HF patients. We found that early anti-IL-1β treatment transiently increased cardiac infiltration of CD206 + macrophages and delayed left ventricular (LV) dilation, which however did not suffice to prevent HF development at 8 weeks post-TAC. In contrast, late anti-IL-1β treatment did not alter LV dilation, but reduced cardiac lymphangiogenesis. This was linked to a cell non-autonomous role of IL-1β in promoting cardiac lymphangiogenesis through stimulation of macrophage production and maturation of VEGF-C. Surprisingly, despite reduced lymphatic density in late anti-IL-1β-treated mice, cardiac inflammation, interstitial fibrosis, and HF development were not aggravated. Further, we found that perivascular lymphatic density, unaltered by anti-IL-1β, was negatively associated with perivascular fibrosis in HF patients and our TAC model. In conclusion, IL-1β blockage elicited transient functional cardiac benefit when initiated before LV dilation post-TAC in mice. In contrast, late treatment reduced cardiac lymphangiogenesis but did not impact HF development. Our study suggests that the therapeutic window for anti-IL-1β treatment may be crucial, as initiation of treatment during the late lymphangiogenic response, induced by LV dilation, may diminish the potential cardiac benefit in HF patients. Finally, our data support a role of perivascular lymphangiogenesis in limiting perivascular fibrosis.

Dates et versions

hal-05015402 , version 1 (01-04-2025)

Identifiants

Citer

C. Heron, T. Lemarcis, O. Laguerre, M. Bundalo, C Valentin, et al.. Blocking Interleukin-1β transiently limits left ventricular dilation and reduces cardiac lymphangiogenesis during pressure-overload in mice. 2025. ⟨hal-05015402⟩
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