Biology subjects

Ruedl, C.

Publications and source records attributed to Ruedl, C..

5 recordsLinked to original sources

bioRxiv2025

The synovial lining macrophage layer develops in the first weeks of life in a CSF1- and TGFβ- dependent but monocyte-independent process.

Synovial joints harbor a protective lining layer, consisting of fibroblasts and macrophages, which form an epithelial-like barrier. In inflamed joints, lining macrophages regulate both early inflammatory cell influx and resolution. Despite these critical functions, it is currently unknown at what stage during development the synovial macrophage lining is established, and which signals drive this process. Here, we use a combination of genetic models and in vivo perturbations, single cell transcriptomics and imaging to delineate the process of lining formation in mice. We find that the synovial lining is immature at birth and becomes established within the first 3 weeks of life. In this window, the lining is gradually populated with macrophages that originate from fetal sources, proliferate and acquire the lining-specific transcriptional identity. In contrast, monocytes contribute only minimally to the developing lining, and their input remains limited in healthy adulthood. We identify CSF1 and TGF{beta} as key signals in this process, which also involves mechanosensing through PIEZO1. Our study thus identifies the early postnatal window as a critical period for lining macrophage development, with potential lifelong impact on joint health and disease.

immunology↗

bioRxiv2024

Gut microbiota-derived GlcNAc-MurNAc is a TLR4 agonist that protects the host gut

Gut microbiota-derived peptidoglycan fragments (PGNs) are key signaling molecules that regulate multiple aspects of the hosts health. Yet the exact structures of natural PGNs in hosts have not been fully elucidated. Herein, we developed an LC-HRMS/MS analytical platform for global quantification and profiling of natural PGN subtypes in host gut and sera, unexpectedly revealing the abundance of PGN-derived saccharide moieties that do not resemble canonical ligands of mammalian NOD1/2 receptors. Focusing on the disaccharide GlcNAc-MurNAc (GM), a natural gut PGN that does not activate NOD1/2 yet still exhibits robust immunostimulatory effects in host immune cells, we unambiguously established GM as a TLR4 agonist, adding to the growing knowledge of NOD-independent mechanisms of PGN sensing in hosts. Importantly, the administration of GM effectively mitigates colonic inflammation in the DSS-induced colitis model in mice via TLR4-dependent mechanisms, highlighting the in vivo significance of natural gut microbiota-derived PGNs in maintaining host intestinal homeostasis.

biochemistry↗

bioRxiv2024

Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers

Hyper-activation of the canonical Wnt signaling pathway drives small intestine and colon tumors. As the major Wnt pathway effector in healthy intestines, TCF7L2 is a suspected oncogene in both cancer types. However, this has been challenging to verify because Tcf7l2 knockout is lethal. To circumvent lethality, we generated a novel transgenic mouse that allows dose-dependent, systemic, inducible and reversible repression of endogenous Tcf7l2 expression. Using this mouse, we demonstrate that TCF7L2 is essential for early adenoma development in the small intestine (ApcMin/+ mouse model) but not colon (DSS-treated ApcMin/+ mouse model). Once established however, neither small intestine nor colon adenomas require TCF7L2 for maintenance. Despite this, Tcf7l2 repression rescues both types of cancer mice from lethal cachexia--a prevalent cancer comorbidity characterized by debilitating weight loss and skeletal muscle atrophy. In colon cancer cachexia, elevated TCF7L2 in the gastrocnemius muscle induces atrophy by activating the transcription of multiple atrophy genes within the ubiquitin-proteasome and autophagy-lysosome systems. Hence, repressing Tcf7l2 normalizes atrophy gene expression back to non-cachectic expression levels and restores muscle mass. The cachexia recovery mechanism in small intestine cancer remains undefined but is independent of the gastrocnemius. This study shows that systemic and partial Tcf7l2 repression is both well-tolerated and effective in rescuing moribund cancer mice from cachexia-induced death. Hence this is a promising treatment strategy for cancer patients suffering from cachexia. Additionally, our transgenic mouse is a valuable tool to study muscle atrophy across other conditions including aging, diabetes and neuromuscular disease.

cancer biology↗

bioRxiv2020

Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population

Dendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the LNs. These LClike cells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClike cells together with cDC1s were the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.

immunology↗

bioRxiv2019

Islet macrophages drive islet remodeling and compensatory hyperinsulinemia in the early diabetes

{beta}-cells respond to peripheral insulin resistance by increasing circulating insulin in early type-2 diabetes (T2D). Islet remodeling supports this compensation but the drivers of this process remain poorly understood. Infiltrating macrophages have been implicated in late stage T2D but relatively little is known on islet resident macrophages, especially in early T2D. We hypothesize that islet resident macrophages contribute to islet vascular remodeling and hyperinsulinemia, the failure of which results in a rapid progression to T2D. Using genetic and diet-induced models of compensatory hyperinsulinemia we show that its depletion significantly compromises islet remodeling in terms of size, vascular density and insulin secretion capacity. Depletion of islet macrophages reduces VEGF-A secretion from both human and mouse islets ex vivo and the impact of reduced VEGF-A functionally translates to delayed re-vascularization upon transplantation in vivo. Hence, we show a new role of islet resident macrophages in the context of early T2D and suggest that there is considerable utility in harnessing islet macrophages to promote islet remodeling and islet insulin secretion capacity.\n\nHighlightsO_LIThe compensatory hyperinsulinemic phase of type-2 diabetes is accompanied with significant pancreatic islet remodeling.\nC_LIO_LIBona fide islet resident macrophages are increased during the diabetic compensation phase by largely in situ proliferation.\nC_LIO_LIAblating macrophages severely compromises the islet remodeling process and exacerbates glycemic control in vivo.\nC_LIO_LIMouse and human islet macrophages contribute VEGF-A to the islet environment.\nC_LIO_LISpecific removal of islet macrophages delays islet vascularization in compensatory hyperinsulinemic mice.\nC_LI

molecular biology↗