Biology subjects

Smith, A. A. T.

Publications and source records attributed to Smith, A. A. T..

4 recordsLinked to original sources

bioRxiv2024

Holding glycolysis in check though Alox15 activity is required for macrophage M2 commitment and function in tissue repair and anti-helminth immunity.

Macrophage polarization by type-2 cytokines is central to anti-helminth immunity and tissue repair. While some hallmark changes in macrophages are well-characterized and associated with protection against helminths, it is still unclear how macrophages exert their anti-helminth effects. In this context, we investigated Arachidonate 15-lipoxygenase (Alox15), a lipoxygenase well known for its role in macrophage polarization in the context of metabolic diseases, and a hallmark of type-2 macrophage (M2) human polarization. We show that in the absence of Alox15, M2 cannot trap and kill helminths. Surprisingly, expression of M2 markers was normal despite a loss of function. Instead, we found a concomitant increase in pro-inflammatory responses due to an uncontrolled activation of glycolysis. We further show that activation of Peroxisome proliferator-activated receptor-delta (PPAR-{delta}) by lipids downstream of Docosapentaenoic acid (DPA) can restore normal glycolysis control, highlighting a novel role for lipids in the fine-tuning of the metabolic support required for optimal macrophage polarization.

immunology↗

bioRxiv2023

An immune cell lipid atlas reveals the basis of susceptibility to ferroptosis

The cellular lipidome is comprised of thousands of unique lipid species. This complexity underpins the many roles of lipids in cellular biology. How lipidome composition varies between cell types and how such differences contribute to cell-specific functionality is poorly understood. Here, using mass spectrometry-based targeted lipidomics, we have characterised the cellular lipid landscape of the human and mouse immune systems (www.cellularlipidatlas.com). We find that myeloid and lymphoid cell lineages have unique lipid compositions, notably in the usage of ester and ether bonds within glycerophospholipids (PLs) and PL acyl chain composition. To determine if immune cell-specific lipid phenotypes promote cell-specific functional properties we focused on differences in poly-unsaturated fatty acid (PUFA)-containing PL, the levels of which are markedly higher in lymphoid cells relative to myeloid cells. We firstly show that differences in PUFA-PL content provides a mechanistic basis for previously described differences in immune cell susceptibility to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, and secondly, that the low PUFA-PL content of neutrophils restrains NADPH oxidase-driven ferroptosis. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

cell biology↗

bioRxiv2021

Developmental and Intergenerational Landscape of Human Circulatory Lipidome and its Association with Obesity Risk

Lipids play a vital role in human health and development, but changes to their circulatory levels during gestation and in early life are poorly understood. Here we present the first developmental and intergenerational landscape of the human circulatory lipidome, derived by profiling of 480 lipid species representing 25 lipid classes, in mothers and their offspring (n=2491). Levels of 66% of the profiled lipids increased in maternal circulation during gestation, while cord blood had higher concentrations of acylcarnitines and lysophospholipids. The offspring lipidome at age six years revealed striking similarities with postnatal maternal lipidome (adult) in its lipid composition and concentrations. Comparison of lipids associated with child and maternal adiposity identified a 92% overlap, implying intergenerational similarities in the lipid signatures of obesity risk. We also catalogued lipid signatures linked with maternal adiposity during gestation and offspring birthweight, and validated (>70% overlap) the findings in an independent birth-cohort (n=1935).

systems biology↗

bioRxiv2019

The contribution of lincRNAs at the interface between cell cycle regulation and cell state maintenance

Cell cycle progression requires dynamic and tightly-regulated transitions between well-defined cell cycle stages. These transitions are controlled by the interplay of established cell cycle regulators. Changes in the activity of these regulators are thought to underpin differences in cell cycle kinetics between distinct cell types. Here, we investigate whether cell type-specific long intergenic noncoding RNAs (lincRNAs) contribute to embryonic stem cell adaptations, which have been shown to be essential for the maintenance of embryonic stem cell state. We used single cell RNA-sequencing data of mouse embryonic stem cells (mESC) staged as G1, S, or G2/M to identify genes differentially expressed between these phases. We found differentially expressed lincRNAs to be enriched amongst cell cycle regulated genes. These cell cycle associated lincRNAs (CC-lincRNAs) are co-expressed with protein-coding genes with established roles in cell cycle progression. Interestingly, 70% of CC-lincRNAs are differentially expressed between G1 and S, suggesting they may contribute to the maintenance of the short G1 phase that characterizes the embryonic stem cell cycle. Consistent with this hypothesis, the promoters of CC-lincRNAs are enriched in pluripotency transcription factor binding sites, and their transcripts are frequently co-regulated with genes involved in the maintenance of pluripotency. We tested the impact of 2 CC-lincRNA candidates and show that modulation of their expression is associated with impaired cell cycle progression, further underlining the contribution of mESC-specific lincRNAs to cell cycle modulation in these cells.

genomics↗