Biology subjects

Schiessl, I.

Publications and source records attributed to Schiessl, I..

4 recordsLinked to original sources

bioRxiv2025

Heparan sulfate glycosaminoglycans mediate CXCL4 (PF4) transport across the blood-brain barrier and effects on neurogenesis

CXCL4 (PF4) is a chemokine stored in platelets that has pleiotropic effects across biological settings. These effects include driving of inflammation and fibrosis as well as reversal of the effects of ageing. We have recently demonstrated that CXCL4 function is driven, independently of known chemokine receptors, through binding to glycosaminoglycan (GAG) side chains on proteoglycans within the cell surface glycocalyx. In this study, we have used intravital imaging and radioactive tracer studies, in combination with an exogenous inhibitor and a GAG-binding CXCL4 mutant, to demonstrate that CXCL4 can enter the brain parenchyma of mice by binding to proteoglycans within the cell surface of the endothelial glycocalyx of the blood-brain barrier (BBB). Furthermore, we have also demonstrated that CXCL4 directly promotes neurogenesis in vitro, which is mediated by its ability to oligomerise and bind to GAGs. These findings provide a molecular mechanism for CXCL4 uptake and function within the brain. Furthermore, these data have important implications for understanding CXCL4 during health and disease that may enable development of CXCL4-related therapeutics for inflammatory diseases and ageing.

neuroscience↗

bioRxiv2022

Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread non-receptor mediated immune cell recruitment

Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system, but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation, due to a lack of mechanistic understanding. Specifically, CXCL4 (PF4) has no established receptor that explains its function. Here we use biophysical, in vitro and in vivo techniques to determine the mechanism underlying CXCL4 mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars within the endothelial extracellular matrix resulting in increased vascular permeability and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulphation confers selectivity onto chemokine localisation. These findings represent a new understanding of chemokine biology, providing novel mechanisms for future therapeutic targeting. One sentence summaryCXCL4 binds to extracellular matrix proteoglycans resulting in increased vascular permeability and recruitment of a wide range of different leukocytes via a non-canonical mechanism.

immunology↗

bioRxiv2022

Sensory adaptation in the barrel cortex during active sensation in the awake, behaving mouse

Sensory adaptation (SA) is a prominent aspect of how neurons in anaesthetised animals respond to sensory signals, ubiquitous across species and modalities. However, SA depends on the activation state of the brain and it has been doubted whether SA is expressed in behaving animals. Here, we addressed this question by training mice to detect an object using their whiskers and recording neuronal activity from barrel cortex whilst simultaneously imaging the whiskers in 3D. We found that neuronal responses decreased during the course of whisker-object touch sequences but that this was due to two factors. First, a motor effect, whereby, during a sequence of touches, later touches were mechanically weaker than early ones. Second, a sensory encoding effect, whereby neuronal tuning to touch became progressively less sensitive during the course of a touch sequence. The sensory encoding effect was whisker-specific. These results show that SA does occur during active whisker sensing and suggest that SA is fundamental to sensation during natural behaviour.

neuroscience↗

bioRxiv2019

Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

The development of new therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair.\n\nThese findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify for the first time two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of new stroke treatments.

neuroscience↗