Biology subjects

Rot, A.

Publications and source records attributed to Rot, A..

4 recordsLinked to original sources

bioRxiv2026

Erythroblast-derived mediators program neutrophil development and function

Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defence. The mechanisms that maintain a balanced regulation of neutrophil effector functions during this process remain incompletely understood. Here, we identify bone marrow-resident erythroblasts as a key source of specialized pro- resolving mediators (SPMs) and show that they imprint neutrophil development and function. Terminally differentiating erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes including augmented release of reactive oxygen species and neutrophil extracellular traps and increased migration to chemotactic stimuli, leading to increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in DSS-colitis. Aberrant neutrophil phenotypes were rectified by the reconstitution of RvD5n-3 DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting the involvement of the macrophage niche in mediating the SPM effects on granulopoiesis. Our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses. Key PointsErythroblasts are a source of Alox15-dependent SPMs that regulate BM erythroblastic island integrity and neutrophil maturation and function Loss of erythroblast Alox15 disrupts neutrophil development and function, defects that are restored add-back of RvD5n-3 DPA.

immunology↗

bioRxiv2026

Mapping vascular plasticity in liver fibrogenesis identifies novel fibrosis-associated endothelial cells in early-stage liver disease

Vascular plasticity is a crucial biological asset enabling our bodies to rapidly adapt to infections and acute inflammation. However, repeated insult during chronic disease can result in these vascular adaptations becoming irreversible, thereby driving disease progression and fibrosis. This study aimed to understand if phenotypic changes in endothelial cell (EC) identity could be indicative of progressive fibrosis and thereby offer new diagnostic and therapeutic opportunities for patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Previous research has documented that a significant shift in EC transcriptomic signature occurs during liver fibrosis in both pre-clinical models and patients. However, the protein expression profile, phenotype and functional role of these new EC subpopulations that are induced during fibrogenesis is unclear. In this study, we integrate high-resolution imaging, proteomic and transcriptomic analysis which collectively highlight a central role for endothelial-to-mesenchymal transition (EndMT)-induced EC plasticity in the derivation of fibrosis-associated EC (FAEC). We demonstrate that: 1) full spectrum flow cytometry can provide new opportunities to categorize and phenotype EC subpopulations, 2) two distinct EndMT-derived FAEC subpopulations expand during fibrogenesis; THY1.2+ICAM1+ and TAGLN+MCAM+ EC that display unique immunomodulatory and metabolic phenotypes, 3) TAGLN+ FAEC are a conserved, pro-fibrotic cell type arising at early stages of MASLD, and 4) increased hepatic expression of TAGLN is significantly associated with detrimental patient outcomes at all stages of liver disease. This study will pave the way for the development of FAEC-specific diagnostic and therapeutic approaches to tackle progressive fibrotic disease. One Sentence SummaryPhenotyping fibrosis-associated endothelial cells reveals pro-fibrotic and immunomodulatory subpopulations at early stages of liver disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/710459v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@dc91fforg.highwire.dtl.DTLVardef@f526d9org.highwire.dtl.DTLVardef@c9783borg.highwire.dtl.DTLVardef@f469e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Specialized mesenteric lymphatic capillaries by-pass the mesenteric lymph node chain to transport peritoneal antigens directly into mediastinal lymph nodes.

Lymphatic vessels (LVs) are indispensable for tissue fluid homeostasis and immune cell trafficking. The network of LVs that channel fluids from the gut into mesenteric lymph nodes (MLN) has been recognized as the sole lymphatic system in the mesentery. Here we describe an alternative, functionally autonomous set of capillary mesenteric LVs (capMLVs) that by-pass the MLNs and drain directly into mediastinal LNs. CapMLVs develop perinatally from valves of collective mesenteric lymphatic vessels (colMLVs) in response to arterial endothelial cell-derived VEGF-C. Once extended, capMLVs detach from colMLVs to form an independent elongated network comprised of LYVE1+, CCL21+ endothelial cells. Avascular areas of the mesentery juxtaposed to capMLVs contain cell islets that express ACKR4. This CCL21-scavenging atypical receptor facilitates the migration of mesenteric phagocytes into capMLVs to be channeled directly into mediastinal LNs. This allows peritoneum-derived ominous antigens to be processed separately from alimentary antigens.

developmental biology↗

bioRxiv2020

Memory-like B cells emerging from germinal centres recycle through the subcapsular sinus

Infection or vaccination leads to the development of germinal centers (GCs) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. We followed the migratory pathways of B cells emerging from germinal centers (BEM) and found that many migrated into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From there, B cells may exit the lymph node to enter distant tissues. Some BEM cells interacted with and took up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibited the recycling of BEM cells and resulted in less efficient adaption to antigenic variation. Our findings suggest that the recycling of BEM cells, that transport antigen and that contain the genetic code for B cell receptor variants, may support affinity maturation to antigenic drift.

immunology↗