Biology subjects

Wienecke, L. M.

Publications and source records attributed to Wienecke, L. M..

3 recordsLinked to original sources

bioRxiv2026

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis

Cardiac fibrosis is causally linked to heart failure progression and survival. Currently, there are no approved treatments that directly target cardiac fibrosis. Recent studies have identified a subset of activated cardiac fibroblasts distinct from myofibroblasts that are marked by fibroblast activation protein (FAP) expression, emerge in the injured and diseased heart through inflammatory signaling, and contribute to fibrosis. Using a genetic mouse model, we demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE(R) molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced remodeling, and increased scar size. FAP BiTE(R) molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg; and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Mechanistically, we reveal that IFNg; signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE(R) molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE(R) molecules and inform the design of the next generation of therapeutics.

immunology↗

bioRxiv2026

Tricuspid valve regurgitation accelerates heart failure via a cardio-intestinal innate immune circuit

Activation of the immune system impacts the progression of heart failure (HF), but the underlying mechanisms remain incompletely understood. Here, we identify a cardio-intestinal innate immune axis that links systemic venous congestion to myocardial inflammation, fibrosis, and functional decline. Using single-cell and single-nucleus transcriptomic profiling in patients and mice with tricuspid regurgitation (TR), we demonstrate that TR disrupts intestinal barrier integrity and elicits expansion of circulating monocytes which in turn orchestrate pathological crosstalk between the right and left heart. Monocyte-derived Interleukin-6 (IL-6) emerged as a key mediator of TR-driven myocardial fibrosis and dysfunction. Blockade of IL-6 attenuated cardiac fibrosis and improved cardiac function. In patients, catheter-based repair of TR resulted in reduced IL-6 levels. Together, these findings establish cardio-intestinal innate immunity as a mechanism linking altered hemodynamics to left ventricular remodeling and nominate TR patients as a selective target population for IL-6-directed therapy in HF. One Sentence SummaryThis work mechanistically resolves the heart-gut axis in tricuspid valve regurgitation, and its impact on heart failure progression as mediated by Interleukin-6.

immunology↗

bioRxiv2023

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in murine heart failure with preserved ejection fraction

Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chigh macrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNF[a]. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.

cell biology↗