Biology subjects

Michel, J.-B.

Publications and source records attributed to Michel, J.-B..

3 recordsLinked to original sources

bioRxiv2023

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

Blocking pro-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 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-1{beta} treatment during HF development following pressure-overload induced by transaortic constriction (TAC) in BALB/c mice. We also examined the impact of IL-1{beta} 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-1{beta} 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-1{beta} treatment did not alter LV dilation, but reduced cardiac lymphangiogenesis. 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 HF development were not aggravated. Further, we found that perivascular lymphatic density, unaltered by anti-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 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-1{beta} 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.

physiology↗

bioRxiv2022

Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression

AimsIgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression. Methods and ResultsThrough histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression. ConclusionsOur data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

pathology↗

bioRxiv2021

Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure

RationaleLymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphatics in non-ischemic cardiomyopathy induced by pressure-overload remains to be determined. ObjectiveInvestigate cardiac lymphangiogenesis following transverse aortic constriction (TAC) in adult male or female C57Bl/6J or Balb/c mice, and in patients with end-stage HF. Methods & ResultCardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, edema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis, respectively. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice. The gender- and strain-dependent mouse cardiac hypertrophic response to TAC, especially increased ventricular wall stress, led to lymphatic expansion in the heart. Our experimental findings that ventricular dilation triggered cardiac lymphangiogenesis was mirrored by observations in clinical HF samples, with increased lymphatic density found in patients with dilated cardiomyopathy. Surprisingly, the striking lymphangiogenesis observed post-TAC in Balb/c mice, linked to increased cardiac Vegfc, did not suffice to resolve myocardial edema, and animals progressed to dilated cardiomyopathy and HF. Conversely, selective inhibition of the essentially Vegfd-driven capillary lymphangiogenesis observed post-TAC in male C57Bl/6J mice did not significantly aggravate cardiac edema. However, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, while the TAC-triggered development of interstitial cardiac fibrosis was unaffected by anti-VEGFR3, inhibition of lymphangiogenesis increased perivascular fibrosis and accelerated the development of left ventricular dilation and cardiac dysfunction. ConclusionsWe demonstrate for the first time that endogenous cardiac lymphangiogenesis limits pressure-overload-induced cardiac inflammation and perivascular fibrosis, thus delaying HF development. While these findings remain to be confirmed in a larger study of HF patients, we propose that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development.

physiology↗