Lozan Sheriff

University of Birmingham

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Patricia F. Lalor

National Institute for Health Research

David Bending

University of Birmingham

Lewis S. C. Ward

AstraZeneca (United Kingdom)

Abhishek Chauhan

University of Birmingham

Gerard B. Nash

University of Birmingham

Philip N. Newsome

King's College Hospital

Carl Ward

Impulse Dynamics (United States)

Reenam S. Khan

Imperial College London

Jon Frampton

University of Birmingham

David A.J. Lecky

University of Birmingham

Cooperative Institutions

University of Birmingham

NIHR Birmingham Biomedical Research Centre

German Cancer Research Center

National Institute for Health Research

Heidelberg University

University Hospitals Birmingham NHS Foundation Trust

StemCells (United States)

University of Tübingen

Queen Elizabeth Hospital Birmingham

Institute of Immunology

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Nur77-Tempo mice reveal T cell steady state antigen recognition

Discovery Immunology (2022)

Thomas A.E. Elliot Emma Jennings David A.J. Lecky Sophie Rouvray Gillian M. Mackie

Abstract In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. Nr4a3-Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that Nr4a1/Nur77 may be a more sensitive gene to distal TCR signals compared to Nr4a3, so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69+ lymphoid T cells are enriched for FT Blue+ Red+ T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of Nr4a1 to lower TCR signal strengths.

Timer

10.1093/discim/kyac009

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Vancomycin impairs macrophage fungal killing by disrupting mitochondrial morphology and function

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Ebrima Bojang Lozan Sheriff Man Shun Fu Chloe Wellings Ketema Abdissa

Abstract Vancomycin is a widely prescribed antibiotic used in the treatment of Gram-positive bacterial infections. We recently showed that this antibiotic disrupted protective anti-fungal immune responses via microbiome dysbiosis, enhancing susceptibility to invasive candidiasis. Antibiotics are an independent risk factor for developing this life-threatening fungal infection, but whether microbiota-independent mechanisms also drive this association is not clear. Here, we show that vancomycin directly impairs macrophage responses to Candida albicans , the main causative agent of invasive candidiasis. Vancomycin-treated macrophages were less able to kill C. albicans despite normal phagocytosis rates and were hyper-inflammatory and more likely to die during infection. We found that vancomycin bound to macrophage mitochondria, leading to depolarisation, reduced respiratory capacity and a hyper-fragmented morphology associated with increased ROS production. Taken together, this work demonstrates direct effects of vancomycin on mammalian immune cells, helping us to understand pro-inflammatory effects of this drug and how it promotes susceptibility to life-threatening fungal infection.

Morphology

10.1101/2024.06.25.600580

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Adipogenic Differentiation of Mesenchymal Stem Cells Alters Their Immunomodulatory Properties in a Tissue-Specific Manner

Stem Cells (2017)

Hafsa Munir Lewis S. C. Ward Lozan Sheriff Samuel Kemble Saba Nayar

Abstract Chronic inflammation is associated with formation of ectopic fat deposits that might represent damage-induced aberrant mesenchymal stem cell (MSC) differentiation. Such deposits are associated with increased levels of inflammatory infiltrate and poor prognosis. Here we tested the hypothesis that differentiation from MSC to adipocytes in inflamed tissue might contribute to chronicity through loss of immunomodulatory function. We assessed the effects of adipogenic differentiation of MSC isolated from bone marrow or adipose tissue on their capacity to regulate neutrophil recruitment by endothelial cells and compared the differentiated cells to primary adipocytes from adipose tissue. Bone marrow derived MSC were immunosuppressive, inhibiting neutrophil recruitment to TNFα-treated endothelial cells (EC), but MSC-derived adipocytes were no longer able to suppress neutrophil adhesion. Changes in IL-6 and TGFβ1 signalling appeared critical for the loss of the immunosuppressive phenotype. In contrast, native stromal cells, adipocytes derived from them, and mature adipocytes from adipose tissue were all immunoprotective. Thus disruption of normal tissue stroma homeostasis, as occurs in chronic inflammatory diseases, might drive “abnormal” adipogenesis which adversely influences the behavior of MSC and contributes to pathogenic recruitment of leukocytes. Interestingly, stromal cells programmed in native fat tissue retain an immunoprotective phenotype.

Adipose tissue macrophages

10.1002/stem.2622

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Citations (54)

Nuclear Factor \(\kappa\)B transcriptional regulator function in haemopoietic stem cells

Lozan Sheriff

The NF-\(\kappa\)B family of transcription factors are essential for different stages of murine haemopoiesis as supported by studies on single or double knockout mice. The function of NF-\(\kappa\)B1 and NF-\(\kappa\)B2 in haemopoietic stem cells (HSCs) has never been described before. In mice, the bone marrow c-Kit+Sca1+Lin- (KSL) population represent HSCs that have the ability to repopulate the bone marrow of lethally irradiated animals. Using knockout mice technology we were able to study the function of NF-\(\kappa\)B1 and NF-\(\kappa\)B2 in HSCs by performing amongst others transplantation assays, which is the most precise way to test HSC potential. Nf\(\kappa\)b1-/- KSL cells are fully able to reconstitute lethally irradiated recipients indicating that the in vivo self-renewal capacity is unaffected. In contrast, colony assays showed NF-\(\kappa\)B1 dependency. Upon serial replating, knockout cells were not able to form colonies and lost their in vitro self-renewal capacity. Transplantation of the nf\(\kappa\)b2-/- KSL cells engraft with a proliferative phenotype and a competitive advantage, with changes in the B-cell and myeloid cell lineages. Similar to nf\(\kappa\)b1-/-, nf\(\kappa\)b2-/- KSL cells lose their function as stem cells upon serial replating. These findings highlight the importance of NF-\(\kappa\)B family proteins in HSCs, especially NF-\(\kappa\)B2 and should be considered in the development of future cancer treatment that target NF-B proteins.

Kappa

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Stem Cells (2018)

Catharina Melzer Juliane von der Ohe Ralf Hass Katherine G. Akers Yoan Chérasse

10.1002/stem.2863

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Origin-Specific Adhesive Interactions of Mesenchymal Stem Cells with Platelets Influence Their Behavior After Infusion

Stem Cells (2018)

Lozan Sheriff Asma Alanazi Lewis S. C. Ward Carl Ward Hafsa Munir

We investigated the adhesive behavior of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow MSC (BMMSC) or umbilical cord MSC (UCMSC) adhered efficiently from flow to the matrix proteins, collagen, or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to predeposited platelets. The differences in behavior in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin-induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. Stem Cells 2018;36:1062-1074.

10.1002/stem.2811

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Citations (27)

Uncovering the role of platelets in human paracetamol-induced hepatotoxicity

Toxicology Letters (2021)

Abhishek Chauhan Lozan Sheriff Patricia F. Lalor

Acetaminophen

10.1016/s0378-4274(21)00382-9

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Interferonγ and IL-27 positively regulate type 1 regulatory T-cell development during adaptive tolerance

bioRxiv (Cold Spring Harbor Laboratory) (2024)

David A.J. Lecky Lozan Sheriff Sophie Rouvray L. George Rebecca A. Drummond

Summary Strong T-cell receptor (TCR) and IL-27 signalling influence type-1 regulatory (Tr1) T-cell development but whether other signals determine their differentiation is unclear. Utilising Tg4 TCR transgenic mice we established a model for rapid Tr1 cell induction. A single high dose of [4Y]-MBP peptide drove the differentiation of Il10 + T-cells with bona fide Tr1 cell protein and mRNA signatures. Kinetic transcriptional analysis revealed that the Tr1 cell module was transient and preceded by a burst of Ifng transcription in CD4+ T-cells. Neutralisation of IFNγ reduced Tr1 cell frequency and strong TCR signalling markers, which was correlated with reduced macrophage activation. Antibody depletion experiments inferred that T-cells – but not NK cells – provided the relevant source of IFNγ. Additionally, we show that blocking IL-27 in combination with IFNγ neutralisation additively reduced Tr1 cell frequency in vivo . These findings reveal that during strong tolerogenic TCR signalling IFN-γ has a non-redundant regulatory role in augmenting the differentiation of Tr1 cells in vivo .

10.1101/2024.06.21.598825

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Circulating myeloid populations have prognostic utility in alcohol-related liver disease

Frontiers in Immunology (2024)

Reenam S. Khan Shees Salman Laura Harford Lozan Sheriff Jon Hazeldine

Introduction Alcohol-related liver disease (ARLD) accounts for over one third of all deaths from liver conditions, and mortality from alcohol-related liver disease has increased nearly five-fold over the last 30 years. Severe alcohol-related hepatitis almost always occurs in patients with a background of chronic liver disease with extensive fibrosis or cirrhosis, can precipitate ‘acute on chronic’ liver failure and has a high short-term mortality. Patients with alcohol-related liver disease have impaired immune responses, and increased susceptibility to infections, thus prompt diagnosis of infection and careful patient management is required. The identification of early and non-invasive diagnostic and prognostic biomarkers in ARLD remains an unresolved challenge. Easily calculated predictors of infection and mortality are required for use in patients who often exhibit variable symptoms and disease severity and may not always present in a specialized gastroenterology unit. Methods We have used a simple haematological analyser to rapidly measure circulating myeloid cell parameters across the ARLD spectrum. Results and Discussion We demonstrate for the first time that immature granulocyte (IG) counts correlate with markers of disease severity, and our data suggests that elevated counts are associated with increased short-term mortality and risk of infection. Other myeloid populations such as eosinophils and basophils also show promise. Thus IG count has the potential to serve alongside established markers such as neutrophil: lymphocyte ratio as a simply calculated predictor of mortality and risk of infectious complications in patients with alcohol-related hepatitis. This would allow identification of patients who may require more intensive management.

Liver disease

Chronic liver disease

10.3389/fimmu.2024.1330536

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AFH volume 32 issue 1 Cover and Front matter

The Journal of African History (1991)

Duy Ngoc D R O B I N S O N M M B O D J I Universitede Universitede Provence R O L I V E R

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Front cover

Content (measure theory)

10.1017/s0021853700025299

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