Master of Science
Physiology and Pharmacology
Dr. Wei-Yang Lu
Lung macrophages (LMϕs) play a key role in pulmonary innate immunity. They polarize into different phenotypes adapting to the needs of the immediate pulmonary environment. Studies in our laboratory suggest that murine LMϕs are endowed with an autocrine gamma-aminobutyric acid (GABA) signaling system. My honors thesis study found that antagonizing the autocrine GABA signaling in alveolar macrophages (AMϕs) increased secretion of the M1 cytokine tumor necrosis factor-alpha (TNF-α), suggesting a role for GABA signaling in immune response. This project explored whether GABA signaling plays a role in LMϕ polarization. Results from this study confirmed that bacterial toxin lipopolysaccharide (LPS) and the Th1 cytokine interferon gamma (IFNγ) shifted LMϕs to the pro-inflammatory M1 phenotype, marked by increased expression of inducible nitric oxide synthase (iNOS). On the other hand, the Th2 cytokines interleukin (IL)-4 and IL-13 shifted LMϕs toward the M2 phenotype marked by increased arginase-1. Importantly, in both RAW 264.7 cell line and primary LMϕs, LPS and IFNγ treatment increased iNOS expression while decreasing glutamic acid decarboxylase (GAD) and A-type GABA receptor α2-subunit (α2-GABAAR). Conversely, treatment with IL4/13 induced an upregulation of arginase-1, GAD, and α2-GABAAR. Moreover, treatment of primary LMϕs with IL4/13 and GABAAR antagonist picrotoxin decreased arginase-1 and GAD expression, and increased iNOS levels. These results suggest the autocrine GABA signaling system in LMϕs dynamically changes with their phenotypic polarization. This signaling system functions to limit the M1 response, but facilitate M2 reaction, and thus a change in the GABA signaling may alter the inflammatory responses of these cells.
Poirier, Jacob W., "The Role of GABA Signalling in Lung Macrophage Immune Response" (2016). Electronic Thesis and Dissertation Repository. 4154.