Biology subjects

Hagman, J.

Publications and source records attributed to Hagman, J..

3 recordsLinked to original sources

bioRxiv2022

Alpha-1-antitrypsin binds to the glucocorticoid receptor with biological significance in macrophages

Alpha-1-antitrypsin (AAT), a serine protease inhibitor produced mainly by the liver, is the third most abundant protein in plasma. While a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Since AAT has significant anti-inflammatory properties affecting many cell types including macrophages, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in macrophages. We report the novel finding that AAT binds to GR in macrophages using several approaches, including co-immunoprecipitation, mass spectrometry, microscale thermophoresis, and molecular modeling. The mass spectrometry data are available via ProteomeXchange with identifier PXD030989. We further demonstrate that AAT induction of angiopoietin-like 4 protein and AAT inhibition of lipopolysaccharide-induced nuclear factor-kappa B activation and interleukin-8 production are mediated, in part, through AAT-GR interaction. Furthermore, this interaction contributes to a host-protective role against mycobacteria in macrophages. The interaction of AAT and GR described in this study identifies a mechanism for the antiinflammatory and host-defense properties of AAT.

immunology↗

bioRxiv2020

GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Mast cells (MCs) are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the MC lineage-determining factors (LDTFs). However, it is unclear whether these LDTFs regulate chromatin accessibility at MC enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of MC identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We found that the number and densities of GATA2-but not MITF-bound sites at the super-enhancers were several folds higher than that at the typical enhancers. Our studies revealed that GATA2 promotes robust gene transcription to maintain MC identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key MC genes.

molecular biology↗

bioRxiv2018

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimers disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-dependent navigation is impaired in pre-dementia Alzheimers disease.\n\nForty-five patients with mild cognitive impairment (26 with CSF Alzheimers disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-dependent navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimers Disease.\n\nBiomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57).\n\nThis study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimers disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimers disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimers drugs.

neuroscience↗