Biology subjects

Lemnitzer, P.

Publications and source records attributed to Lemnitzer, P..

3 recordsLinked to original sources

bioRxiv2026

Time-restricted feeding exacerbates liver fibrosis by promoting BDH1-mediated ketolysis in hepatic stellate cells.

Time-restricted feeding (TRF) is widely considered metabolically beneficial, yet its impact on chronic liver disease progression remains poorly defined. This study investigates the effects of TRF on liver fibrogenesis. Using carbon tetrachloride (CCl4)-induced, bile duct ligation (BDL)-induced, and choline-deficient, L-amino acid-defined high-fat diet (CDAHFD)-induced murine models of liver fibrosis, we demonstrate that TRF consistently exacerbates fibrotic injury. Mechanistically, TRF induces the systemic elevation of the ketone body {beta}-hydroxybutyrate (BHB). We identify the ketolytic enzyme 3-hydroxybutyrate dehydrogenase 1 (BDH1) as a critical mediator of this process within hepatic stellate cells (HSCs). BDH1 expression is markedly upregulated in activated HSCs, enabling these cells to metabolize BHB. This BDH1-dependent ketolysis redirects BHB-derived carbons into the tricarboxylic acid cycle, supplying acetyl-CoA and citrate to drive de novo lipogenesis and support a profibrogenic metabolic state. Both the genetic ablation of Bdh1 specifically in HSCs and the inhibition of hepatic ketogenesis successfully abolished the pro-fibrotic effects of TRF and exogenous BHB administration. Conversely, exogenous BHB alone was sufficient to recapitulate the exacerbated fibrotic phenotype observed with TRF. These findings reveal a context-dependent, detrimental role for TRF during chronic liver injury, driven by BDH1-mediated metabolic reprogramming in HSCs. Consequently, dietary interventions that elevate systemic ketone bodies should be approached with caution in the setting of active liver fibrosis.

cell biology↗

bioRxiv2025

CCR2+ neutrophils exhibit a proinflammatory phenotype and promote plaque destabilization

BackgroundAtherosclerotic plaque destabilization is promoted by inflammatory cell recruitment, tissue cell death and mechanical weakening. Neutrophils are key instigators of vascular tissue injury and perpetuation of inflammation, and targeting their actions is a viable therapeutic opportunity. We here identify a distinct subset of activated neutrophils within atherosclerotic lesions that express the chemokine receptor CCR2, which directs their migration toward areas enriched with smooth muscle cells (SMCs) and contributes to plaque instability. MethodsFlow cytometry and single cell transcriptomic analysis of CCR2+ neutrophils within murine and human atherosclerotic plaques. Tracking of CCR2+ neutrophil in hypercholesterolemic Ldlr-/- mice and in mice reconstituted with Ccr2GFP/- bone marrow. In vivo reactive oxygen species (ROS) and neutrophil extracellular trap (NET) analysis in lipopolysaccharide-induced peritonitis. In vitro migration assays of neutrophils deficient for or treated with specific antagonist against chemokine receptors. In vivo neutrophil recruitment and atherosclerotic plaque destabilization analysis upon CCR2 and CCL2 blockade in a model of advanced atherosclerosis in Apoe-/- mice. ResultsCCR2+ neutrophils preferentially populate mouse and human atherosclerotic lesions and displayed a proinflammatory phenotype with enhanced capacity for ROS production and NET release. Genetic deletion or pharmacologic inhibition of CCR2 significantly reduces neutrophil migration and infiltration to the atherosclerotic lesion, reducing their presence in SMC-rich areas. Consistently, neutralization of the CCR2 ligand CCL2 decreased lesional neutrophil numbers and preserved fibrous cap integrity by increasing SMC content and decreasing overall plaque instability. ConclusionsOur data suggest that a subset of CCR2-expressing neutrophils senses SMC-derived CCR2 ligands to infiltrate and destabilize atherosclerotic lesions. These results support the existence of neutrophil functional heterogeneity within the atherosclerotic lesions contributing to alterations of lesion stability. Specific targeting thereof may improve plaque stability without impacting host defense.

immunology↗

bioRxiv2025

Divergent granulopoiesis at extramedullary sites safeguards host defense

Extramedullary organs such as the spleen can assume granulopoiesis as a supportive mechanism to cope with the demands during persistent inflammation. However, the quantitative output of extramedullary granulopoiesis is limited, thus raising the question if the spleen in fact provides neutrophils of a qualitative difference rather than merely contributing to neutrophil numbers. Here we report splenic stress granulopoiesis with distinct production and differentiation trajectories. Myeloid progenitors in the spleen engage in accelerated production of neutrophils with an immature phenotype. Yet, neutrophils generated during persistent stress granulopoiesis are fully competent to exert antimicrobial functions and are necessary to contain bacterial invasion. Activation of type I interferon signaling in the spleen is required for splenic neutrophil production and its loss impairs host defense. Thus, the spleen provides an immunological environment for stress-induced rapid production and priming of highly active neutrophils to meet the demands during infection.

immunology↗