Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Flavell, Richard
Abstract
The mammalian innate immune system uses a variety of pattern recognition receptors (PRRs) to recognize foreign pathogen-associated molecular patterns (PAMPs) and host damage-associated molecular patterns (DAMPs) and transduce the upstream signals from the cell membrane and intracellular receptors to core downstream immunometabolic signaling outcomes, including the secretion of proinflammatory cytokines and the production of critical reactive oxygen species (ROS), reactive carbonyl species (RCS), and reactive nitrogen species (RNS). Orchestration and resolution of these inflammatory outcomes are indispensable to healthy innate immune function. Correspondingly, their dysregulation is associated with various inflammatory diseases and an impaired ability to resolve bacterial and viral infections. Laccase domain-containing 1 (LACC1) protein is a predicted oxidoreductase highly and selectively expressed in inflammatory macrophages. Its genetic mutations are associated with multiple inflammatory diseases, such as inflammatory bowel diseases (IBDs), arthritis, and clearance of microbial infection. However, the major enzymatic activities required for LACC1 functions remain unclear. In this dissertation, I elucidated the biochemical role of LACC1 in mice and humans, characterizing a novel isocyanic acid (HNCO) synthase activity, converting L-citrulline (L-Cit) to L-ornithine (L-Orn), an essential precursor in polyamine biosynthesis, and HNCO, a cytotoxic RCS previously associated with the uraemic syndrome. Since inducible nitric oxide (NO) synthase (iNOS or NOS2) is the primary source of RNS and L-Cit in inflammatory macrophages, LACC1 serves as a previously missing metabolic bridge between proinflammatory NOS2 signaling and polyamine signaling. Thus, its absence or dysfunction results in dysregulated inflammation in mice and humans. In animal models and bone marrow-derived macrophages (BMDMs) infected by Salmonella enterica Typhimurium, I validated the intimate genetic and metabolic connections among NOS2, LACC1, and ornithine decarboxylase 1 (ODC1), the rate-limiting step in polyamine synthesis. Strikingly, LACC1 phenotypes depend on upstream NOS2 and downstream ODC1, and Lacc1-/- chemical complementation with one of its products, L-Orn, could partly restore wild-type (WT) activities. These findings elucidate a central yet unidentified immunometabolism pathway in inflammatory macrophages, explain why its deficiency might contribute to human inflammatory diseases, and suggest that L-Orn or polyamines could serve as nutraceuticals to ameliorate LACC1-associated immunological dysfunctions such as arthritis or inflammatory bowel disease (IBD).1
Recommended Citation
Wei, Zheng, "Decoding Immunometabolism in Inflammatory Macrophages" (2022). Yale Graduate School of Arts and Sciences Dissertations. 770.
https://elischolar.library.yale.edu/gsas_dissertations/770
