Biology subjects

Habicht, J.

Publications and source records attributed to Habicht, J..

7 recordsLinked to original sources

bioRxiv2023

Distinct Functional States of Neutrophils by Actin Disassembly and NF-kB/STAT3 Signaling

Polymorphonuclear neutrophils (PMNs) can differentiate into distinct states, which can either exacerbate or resolve inflammation. Our study shows that mice challenged with TLR agonists exhibited PMN differentiation along two major paths characterized by the expression of CCR5 or PD-L1. Similar differentiation was observed in the blood of severe COVID-19 patients and the synovial fluid of osteoarthritis patients. Prolonged in vitro priming of human PMNs modeled the differentiation paths. Actin disassembly favored CCR5 upregulation, while NF-kB activation stabilized the actin cytoskeleton and suppressed the development of CCR5+ PMNs. Additionally, PD-L1 upregulation was triggered by STAT3 signaling and NF-kB activation. Functionally, CCR5 expressing PMNs were pro-NETotic, while PD-L1+ PMNs showed immunosuppressive functions by inhibiting T cell proliferation via PD1. Together, PMN differentiation depended on the priming conditions, and the balance between actin disassembly and NF-kB/STAT3 activation translated the present micro-milieu into phenotypic and functional diversification of PMNs. SynopsisNeutrophils underwent phenotypical and functional diversification both in vivo and in vitro. Actin disassembly led to the generation of CCR5high neutrophils with increased spontaneous NETosis, whereas NF-kB and STAT3 induced PD-L1 expression with T-cell suppressive properties as a deviation from the default pathway. O_LIPMN of mice challenged with TLR agonists develop two distinct phenotypes, CCR5high and PD-L1high. C_LIO_LICCR5 and PD-L1-defined neutrophil phenotypes were found in blood of patients with severe COVID-19 and in the synovial fluid of osteoarthritis patients. C_LIO_LIIn vitro priming induced a similar bifurcation of PMN phenotypes marked by either CCR5 or PD-L1. C_LIO_LIActin disassembly preceded canonical development of CCR5+ PMN. C_LIO_LINF-kB halted actin disassembly by LPL regulation. C_LIO_LIDuring neutrophil priming, STAT3 aided NF-kB in the expression of PD-L1. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/548975v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@10305f3org.highwire.dtl.DTLVardef@17bada8org.highwire.dtl.DTLVardef@c61021org.highwire.dtl.DTLVardef@14ce7f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Children are full of optimism, but those rose-tinted glasses are fading: reduced learning from negative outcomes drives hyperoptimism in children.

Believing that good things will happen in life is essential to maintain motivation and achieve highly ambitious goals. This optimism bias, the overestimation of positive outcomes, may be particularly important during childhood when motivation must be maintained in the face of negative outcomes. In a learning task, we have thus studied the mechanisms underlying the development of optimism bias. Investigating children (8-9 year-olds), early (12-13 year-olds) and late adolescents (16-17 year-olds), we find a consistent optimism bias across age groups. However, children were particularly hyperoptimistic, with the optimism bias decreasing with age. Using computational modelling, we show that this was driven by a reduced learning from worse-than-expected outcomes, and this reduced learning explains why children are hyperoptimistic. Our findings thus show that insensitivity to bad outcomes in childhood helps to prevent taking on an overly realistic perspective and maintain motivation.

neuroscience↗

bioRxiv2021

Inflammation induces pro-NETotic neutrophils via TNFR2 signaling

Cytokines released during chronic inflammatory diseases induce pro-inflammatory properties in polymorphonuclear neutrophils (PMN). Here we show that in vitro cytokine treatment leads to the development of a subgroup of human PMN expressing CCR5, termed CCR5+ cytokine-induced PMN (CCR5+ cPMN). Auto/paracrine TNF signaling increases intracellular neutrophil elastase (ELANE) abundance and induces NETosis in CCR5+ cPMN. Triggering of CCR5 amplifies NETosis. Membranous TNF (mTNF) outside-in signaling induces the formation of reactive oxygen species, a known activator of NETosis. In vivo, we find an increased number of CCR5+ cPMN in the peripheral blood and inflamed lamina propria of patients with ulcerative colitis (UC) but not Crohns disease (CD). Notably, failure of anti-TNF therapy is associated with higher frequencies of CCR5+ cPMN. In conclusion, we identify a phenotype of pro-NETotic, CCR5 positive PMN present in inflamed tissue in vivo and inducible in vitro. These cells may reflect an important component of tissue damage during chronic inflammation and could be of diagnostic value.

immunology↗

bioRxiv2020

UNC-45A Destabilizes MTs Independent of its Effect on Non-Muscle Myosin II

In invertebrates, UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein: UNC-45B, expressed in muscle cells only and UNC-45A, expressed in all cells and implicated in regulating both Non-Muscle Myosin II (NMII)- and microtubule (MT)-associated functions. Here we show for the first time that: a) in vitro UNC-45A binds to the MT lattice and weakens its integrity leading to MT bending, breakage and depolymerization, b) in cells, UNC-45A overexpression causes loss of MT mass and increase in MT breakages, c) both in vitro and in cells, UNC-45A destabilizes MTs independent of its NMII C-terminal binding domain and destabilization occurs even in presence of the NMII inhibitor blebbistatin. These findings are consistent with a not mutually exclusive but rather dual role of UNC-45A in regulating NMII activity and MT stability. Because many human diseases, from cancer to neurodegenerative diseases, are caused by or associated with deregulation of MT stability our findings have profound implications in both, the biology of MTs as well as the biology of human diseases and possible therapeutic implications for their treatment.

cell biology↗

bioRxiv2020

Tabula-rasa exploration decreases during youth and is linked to ADHD symptoms

During childhood and adolescence, exploring the unknown is important to build a better model of the world. This means that youths have to regularly solve the exploration-exploitation trade-off, a dilemma in which adults are known to deploy a mixture of computationally light and heavy exploration strategies. In this developmental study, we investigated how youths (aged 8 to 17) performed an exploration task that allows us to dissociate these different exploration strategies. Using computational modelling, we demonstrate that tabula-rasa exploration, a computationally light exploration heuristic, is used to a higher degree in children and younger adolescents compared to older adolescents. Additionally, we show that this tabula-rasa exploration is more extensively used by youths with high attention-deficit/hyperactivity disorder (ADHD) traits. In the light of ongoing brain development, our findings show that children and younger adolescents use computationally less burdensome strategies, but that an excessive use thereof might be a risk for mental health conditions.

neuroscience↗

bioRxiv2020

Noradrenaline modulates tabula-rasa exploration

An exploration-exploitation trade-off, the arbitration between sampling a lesser-known against a known rich option, is thought to be solved using computationally demanding exploration algorithms. Given known limitations in human cognitive resources, we hypothesised the presence of additional cheaper strategies. We examined for such heuristics in choice behaviour where we show this involves a value-free random exploration, that ignores all prior knowledge, and a novelty exploration that targets novel options alone. In a double-blind, placebo-controlled drug study, assessing contributions of dopamine (400mg amisulpride) and noradrenaline (40mg propranolol), we show that value-free random exploration is attenuated under the influence of propranolol, but not under amisulpride. Our findings demonstrate that humans deploy distinct computationally cheap exploration strategies and where value-free random exploration is under noradrenergic control. Data and materials availabilityData and code will be provided upon acceptance.

neuroscience↗

bioRxiv2019

UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs

UNC-45A is a ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system. However, emerging studies from both our and other laboratories support a role of UNC-45A outside of actomyosin regulation. This includes studies showing that UNC-45A: regulates gene transcription, co-localizes and biochemically co-fractionates with gamma tubulin and regulates centrosomal positioning, is found in the same subcellular fractions where MT-associated proteins are, and is a mitotic spindle-associated protein with MT destabilizing activity in absence of the actomyosin system.\n\nHere, we extended our previous findings and show that UNC45A is variably expressed across a spectrum of cell lines with the highest level being found in HeLa cells and in ovarian cancer cells inherently paclitaxel-resistant. Furthermore, we show that UNC-45A is preferentially expressed in epithelial cells, localizes to mitotic spindles in clinical tumor specimens of cancer and co-localizes and co-fractionates with MTs in interphase cells independent of actin or myosin.\n\nIn sum, we report alteration of UNC45A localization in the setting of chemotherapeutic treatment of cells with paclitaxel, and localization of UNC45A to MTs both in vitro and in vivo. These findings will be important to ongoing and future studies in the field that further identify the important role of UNC45A in cancer and other cellular processes.

cell biology↗