Biology subjects

Heron, C.

Publications and source records attributed to Heron, C..

4 recordsLinked to original sources

bioRxiv2026

Mucosal-Associated Invariant T Cells Promote Atherosclerosis Through Monocyte-Driven Inflammation

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes that may contribute to inflammatory responses, although their specific role in atherosclerosis remains poorly understood. In this study, we identified MAIT cells within human atherosclerotic plaques and found that they were significantly enriched among CD3 T cells in plaques compared to matched peripheral blood samples. MAIT cells within plaques exhibited an activated phenotype and showed upregulation of genes associated with inflammation and cellular activation, compared to circulating MAIT cells from the same patients. Using murine models, we found that low-density lipoprotein receptor (Ldlr)-/- mice carrying the CAST locus, which confers naturally higher frequencies of MAIT cells, displayed increased MAIT cell accumulation in both the liver and atherosclerotic plaques when fed a high-cholesterol diet. In contrast, MAIT cell-deficient Ldlr-/-CAST MR1-/- mice exhibited a reduced atherosclerotic burden, diminished liver fibrosis, smaller myocardial infarcts following coronary artery ligation, without significant changes in plasma cholesterol levels. These atheroprotective effects were accompanied by lower monocyte counts in the bone marrow and blood, as well as reduced plaque macrophage accumulation in the plaques. Furthermore, deletion of CCR2, which impairs monocyte mobilization, abrogated the pro-atherogenic effects of MAIT cells, indicating that MAIT-driven atherogenesis occurs through a monocyte-dependent mechanism. Taken together, these findings identify MAIT cells as active contributors to vascular inflammation and position them as potential therapeutic targets for atherosclerosis and its complications.

immunology↗

bioRxiv2025

Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Cardiac lymphatics have emerged as potential targets in cardiovascular diseases (CVDs). However, we recently reported that despite extensive lymphatic expansion during experimental cardiac pressure-overload, lymphatic drainage remained insufficient. To unravel the cellular and molecular mechanisms underlying lymphatic dysfunction in CVDs, we applied cardiac single-cell (sc) analyses in a murine heart failure model. Transaortic constriction (TAC), in C57BL/6J and BALB/c mice, was used to model chronic pressure-overload-induced cardiac hypertrophy and heart failure, respectively. Cardiac lymphatic (LEC) and blood vascular (BECs) endothelial cells were analyzed by scRNAseq (10XGenomics). Lymphatic targets were validated by immunohistochemistry and wholemount-imaging, and in vitro using human LEC cultures. We identified three distinct cardiac lymphatic subpopulations, capillary (LEC1), precollector (LEC2), and valvular (LEC3) clusters, and several BECs clusters, including venous BEC (vBEC). Chronic pressure-overload led to expansion of lymphatic capillaries and loss of valves in BALB/c, but not C75BL6/J. Analysis of differentially expressed genes (DEG) post-TAC revealed reduction only in BALB/c of lymphatic cell-junction components. In contrast, LEC expression of anchoring filaments, immune cell-adhesion molecules, and chemokines was preserved, or increased, indicating functional lymphatic-mediated immune cell uptake post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)-1{beta}-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier properties may underly poor drainage capacity during pressure-overload, despite potent lymphangiogenesis and preserved LEC immune attraction. Further studies are needed to address how to restore lymphatic health to accelerate resolution of both inflammation and edema in CVDs.

cell biology↗

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↗

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↗