Biology subjects

Edwards-Hicks, J.

Publications and source records attributed to Edwards-Hicks, J..

3 recordsLinked to original sources

bioRxiv2022

Resident T cells orchestrate adipose tissue remodeling in a site peripheral to infection

Infection with helminth parasites can affect adiposity, but underlying mechanisms that regulate this process are unclear. We found that fat content of mesenteric adipose tissue (mAT) declined in mice during infection with gut-restricted parasitic worms. This was associated with the accumulation of metabolically activated, immunostimulatory cytokine- and extracellular matrix-secreting multipotent stromal cells, which had potential to differentiate into preadipocytes. Concomitantly, mAT became infiltrated with Th2 lymphocytes that took up long-term residence and responded to signals from stromal cells by producing stromal cell-stimulating cytokines, including Amphiregulin. Signals delivered by Amphiregulin to stromal cells were required for immunity to infection. Our findings reveal intricate intercellular communication between Th2 cells and adipocyte progenitors and link immunity to intestinal infection to T cell-dependent effects on the adipocyte lineage.

immunology↗

bioRxiv2022

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

Necrosis of macrophages in the tuberculous granuloma represents a major pathogenic event in tuberculosis. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanitys most lethal pathogen, is successful in only a minority of infected individuals.

immunology↗

bioRxiv2020

Triacylglycerol synthesis enhances macrophage inflammatory function

Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states1. LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a2. However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development3,4. We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-{gamma} (IFN{gamma}) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1{beta}, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages.

immunology↗