Biology subjects

Huber-Lang, M.

Publications and source records attributed to Huber-Lang, M..

8 recordsLinked to original sources

bioRxiv2026

Loss of C3 and CD14 reduces region-specific neuroinflammation in a murine polytrauma model

BackgroundTraumatic brain injury (TBI) together with non-cerebral injuries characterizes the TBI-polytrauma (P-TBI) constellation, which is associated with acute neurological deterioration, delirium and unfavourable prognosis. It is hypothesized that systemic inflammatory mediators my enhances the focal, cerebral neuroimmune reaction with overall detrimental consequences, in particular in terms of acute microglial reactivity. MethodsWe explored the role of the Complement factor 3 (C3) and of the TLR-co receptor cluster of differentiation (CD14) in a murine polytrauma model that involves a mild TBI together with femur fracture, blunt thorax trauma and resuscitated haemorrhagic shock, making use of mice genetically lacking either C3, CD14 or both. ResultsWe show that P-TBI results in a rapid (4h) and brain-wide induction of inflammatory cytokines, although with distinct profiles (TNF and CCL2 having brain-wide involvement and IL-1{beta} restricted to ipsilateral cortex and striatum). TNF and CCL2 mRNA as well as protein synthesis were upregulated in microglia upon P-TBI in cortex, hippocampus and striatum which was fully abolished in the C3-/-CD14-/-animals. The analysis of single-KO animals revealed that induction of TNF and CCL2 was prevented in animals lacking C3, but not CD14, in the contralateral cortex and striatum, with an abolishment in hippocampus in mice lacking both C3 and CD14. In the cortical area of focal lesion neither C3 nor CD14 affected the induction of pro-inflammatory cytokines. ConclusionThus, C3 and CD14 are dispensable for the acute cytokine response to P-TBI in the site of injury but play differential roles across the cortex, hippocampus and striatum for the induction of cytokines in the non-injured parenchyma and in particular in microglia. Thus, interventions on C3 (mainly) and/or CD14 may reduce the encephalopathy risk associated with P-TBI but not the acute response in the injury site, where additional DAMP signalling may offer redundant activation pathways.

neuroscience↗

bioRxiv2025

Basophils activate splenic B cells and Dendritic cells via IL-13 signaling in acute Traumatic Brain Injury

Peripheral consequences following traumatic brain injury (TBI) are characterized by both systemic inflammatory responses and autonomic dysregulation, with almost all peripheral organs affected. One of the main immune regulatory organs, the spleen, shows high interaction with the brain which is controlled by both circulating mediators as well as autonomic fibers targeting splenic immune cells. The brain-spleen axis does not function as a one-way street, it also shows reciprocal effects where the spleen affects neuroinflammatory and cognitive functions post injury. To date, systemic and splenic inflammatory responses are measured by cells or mediators located in circulation. Nevertheless, most of the signaling and inflammation post injury takes place in the organs. Therefore, we set out to investigate the early signaling landscape in the spleen following TBI, using phospho-proteomic signaling approaches and immunofluorescence stainings to investigate novel molecular and cellular players. Based on the signaling signature, we found a rapid influx of basophil granulocytes towards the spleen, which are recruited via CXCL1 expressed by B-cells and dendritic cells. The basophils activate B cells and dendritic cells (DCs) via the IL-13/IL-13Ra1 signaling pathway to enhance protein translation through the long non-coding RNA NORAD. The early recruitment of basophils and subsequent activation of B cells and DCs, is short lived and sets at 3dpi. Interestingly, the rapid recruitment of basophils is inhibited by ethanol intoxication in TBI. In conclusion, basophils recruitment to the spleen may serve as an early mediator of systemic inflammatory responses to TBI with potential implications for research on biomarkers and therapeutic targets.

neuroscience↗

bioRxiv2024

Pathophysiological response in experimental trauma-related acute kidney injury

BackgroundTrauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. MethodsTo study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI. ResultsThe mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5. ConclusionsOur novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.

pathology↗

bioRxiv2024

The FGFR inhibitor Rogaratinib reduces microglia reactivity and synaptic loss in TBI

BackgroundTraumatic brain injury (TBI) induces an acute reactive state of microglia, which contribute to secondary injury processes through phagocytic activity and release of cytokines. Several receptor tyrosine kinases (RTK) are activated in microglia upon TBI, and their blockade may reduce the acute inflammation and decrease the secondary loss of neurons; thus RTKs are potential therapeutic targets. We have previously demonstrated that several members of the FGFR family are transiently phosporylated upon TBI; the availability for drug repurposing of FGFR inhibitors makes worthwhile the elucidation of the role of FGFR in the acute phases of the response to TBI and the effect of FGFR inhibition. MethodsA closed, blunt, weight-drop mild TBI protocol was employed. The pan-FGFR inhibitor Rogaratinib was administered to mice 30min after the TBI and daily up to 7 days post injury. Phosphor-RTK Arrays and proteomic antibody arrays were used to determine target engagement and large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3 immunostaining were employed for validation. As outcome parameters of the TBI injury immunostainings for NeuN, VGLUT1, VGAT at 7dpi were considered. ResultsInhibition of FGFR during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4 and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was traced back to Iba1+ microglia. Rogaratinib substantially dowregulated the proteomic signature of the neuroimmunological response to trauma, including the expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG. Protracted Rogaratinib treatment exhibited a neuroprotective effect on neuronal density at 7dpi and limited the loss of excitatory (vGLUT+) synapses. ConclusionThe FGFR family is involved in the early induction of reactive microglia in TBI. FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors display potential as microglial modulators in TBI.

neuroscience↗

bioRxiv2022

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

BackgroundTraumatic Brain Injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here we report the effects of blunting neuronal nuclear calcium signals in the context of TBI. MethodsWe used AAV vectors to express the genetically-encoded and nuclear-targeted calcium buffer parvalbumin (PV.NLS.mCherry) or the calcium/calmodulin buffer CaMBP4.mCherry in neurons only. Upon TBI, the extent of neuroinflammation, neuronal death and synaptic loss were assessed by immunohistochemistry and targeted transcriptome analysis. Modulation of the overall level of neuronal activity was achieved by PSAM/PSEM chemogenetics targeted to parvalbumin interneurons. The functional impact of neuronal nuclear Calcium buffering in TBI was assessed by quantification of spontaneous whisking. ResultsBuffering neuronal nuclear calcium unexpectedly resulted in a massive and long-lasting increase in the recruitment of reactive microglia to the injury site, which was characterised by a disease-associated and phagocytic phenotypes. This effect was accompanied by a substantial surge in synaptic loss and significantly reduced whisking activity. Transcriptome analysis revealed a complex effect of TBI in the context of neuronal nuclear calcium buffering, with upregulation of complement factors, chemokines and interferon-response genes, as well as the downregulation of synaptic genes and epigenetic regulators compared to control conditions. Notably, nuclear calcium buffering led to a substantial loss in neuronal osteoprotegerin (OPG). Whereas stimulation of neuronal firing induced OPG expression. Viral re-expression of OPG resulted in decreased microglial recruitment and synaptic loss. OPG upregulation was also observed in the CSF of human TBI patients, underscoring its translational value. ConclusionNeuronal nuclear calcium signals regulate the degree of microglial recruitment and reactivity upon TBI via, among others, osteoprotegerin signals. Our findings support a model whereby neuronal activity altered after TBI exerts a powerful impact on the neuroinflammatory cascade, which in turn contributes to the overall loss of synapses and functional impairment.

neuroscience↗

bioRxiv2022

Zebrafish fin regeneration requires generic and regeneration-specific responses of osteoblasts to trauma

Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-{kappa}B and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics are required for migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established a trauma model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. Successful bone regeneration appears to require the coordinated execution of generic and regeneration-specific responses of osteoblast to trauma. O_FIG O_LINKSMALLFIG WIDTH=131 HEIGHT=200 SRC="FIGDIR/small/481466v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@c1145org.highwire.dtl.DTLVardef@41f525org.highwire.dtl.DTLVardef@4569eaorg.highwire.dtl.DTLVardef@12c85e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Immune system molecules are expressed by neurons, often for unknown functions. We have identified IL-13 and its receptor IL-13Ra1 as neuronal, synaptic proteins in mouse, rat, and human brains, whose engagement upregulates the phosphorylation of NMDAR and AMPAR subunits and, in turn, increases synaptic activity and CREB-mediated transcription. We demonstrate that increased IL-13 is a hallmark of traumatic brain injury (TBI) in mice as well as in two distinct cohorts of human patients. We also provide evidence that IL-13 upregulation protects neurons from excitotoxic death. We show IL-13 upregulation occurring in several cohorts of human brain samples and in CSF. Thus, IL-13 is a previously unrecognized physiological modulator of synaptic physiology of neuronal origin, with implications for the establishment of synaptic plasticity and the survival of neurons under injury conditions. Furthermore, we suggest that the neuroprotection afforded through the upregulation of IL-13 represents a new entry point for interventions in the pathophysiology of TBI.

neuroscience↗

bioRxiv2021

Fast maturation of splenic dendritic cells upon TBI is associated with FLT3/FLT3L signaling

Systemic inflammatory consequences remain a significant burden after traumatic brain injury (TBI), with almost all organs affected. The spleen is connected with the brain by autonomic innervation and by soluble mediators, and the cross-talk between brain and spleen may be important to establish the systemic inflammatory response to TBI. Ethanol intoxication, the most common comorbidity of TBI, is posited to influence the peripheral inflammatory response either directly or through the brain-spleen cross-talk. Here we show that TBI causes a substantial change in transcription of genes associated with dendritic cells activation in the spleen, in particular a FLT3/FLT3L induction 3h after TBI, which was enhanced by EI. The FLT3L induction was associated with the phosphorylation of FLT3 receptor in CD11c+ dendritic cells, which enhanced the protein synthesis of a subset of mRNAs, as shown by the increase in pS6, peIF2A levels in dendritic cells. This corresponded to the upregulation of proteins associated with maturation process and immunostimulatory properties such MHC-II, LAMP1 and CD68, and of pro-inflammatory cytokines such as TNF. Notably, EI enhanced the maturation of dendritic cells. However, whereas TBI decreases expression of the adrenergic 2b receptors on dendritic cells, EI increased it, thus augmenting the chances of cross-talk regulation of immune function by the autonomic system. In conclusion, this data indicates that TBI induces a fast maturation of the immunomodulatory functions of dendritic cells which is associated by FLT3/FLT3L signaling and which is enhanced by EI prior to TBI.

immunology↗