Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Dixit, Vishwa

Abstract

Pro-longevity interventions such as caloric restriction (CR) and methionine restriction (MR) can improve metabolic health. However, despite decades of extensive studies, the mechanisms that underlie the benefits of these dietary interventions are still being characterized. Particularly, the effect of these diets on immune cells in mediating their metabolic benefits has been largely unexplored. This work aimed to expand our understanding of how these dietary interventions may regulate immune responses and identify novel immunomodulatory pathways that could be harnessed during inflammatory and metabolic pathologies.In line with other studies in animal models, we identified that the transsulfuration pathway (TSP) was induced in humans with CR. The TSP controls the synthesis of cysteine from methionine, and produces byproducts such as hydrogen sulfide (H2S). We find that during MR, NLRP3 inflammasome-mediated inflammation can be inhibited by the induction of autophagy due to low availability of sulfur-containing amino acids (SAA). Additionally, the TSP can inhibit NLRP3 inflammasome through the production of H2S. This highlights SAA availability mediated by the TSP as an immunoregulatory checkpoint that may be harnessed to reduce inflammasome-mediated inflammation. However, MR failed to reduce white adipose tissue inflammation in mouse models of acute endotoxemia, Muckle Wells Syndrome, and aging, suggesting that more direct interventions of specific TSP metabolites may need to be explored. In addition to regulation of inflammation, we have found that single amino acid deficiencies can drive extreme thermogenesis in mice, and pathways that protect critical amino acid levels such as the TSP can serve as important checkpoints to defend against unchecked thermogenesis. Using cysteine deficiency as a novel browning model, we find that cysteine deficiency in mice lacking the TSP leads to rapid loss of fat mass and adipose tissue browning. This is mediated by an increase in sympathetic signaling in the adipose tissue, in part through a reduction in the expression of catecholamine degrading enzymes in adipose tissue macrophages. Altogether, this work highlights that regulation of cysteine availability through the TSP serves as an important check point in metabolic and inflammatory homeostasis, and may underlie many of the metabolic benefits during CR. Manipulation of cysteine availability may thus potentiate novel therapeutic strategies for combating inflammatory metabolic diseases such as aging and obesity.

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