In the US alone, asthma affects approximately 39 million individuals and is responsible for over 3,000 deaths annually. Current therapeutic strategies can be ineffective in subgroups of patients, can cause undesired side effects, and treat the symptoms of disease rather than the cause. Greater understanding of the mechanisms that regulate inflammation in the lung is needed in order to direct the development of novel, more selective therapeutic strategies. Recent studies have demonstrated the importance of immune cells called Group 2 innate lymphoid cells (ILC2s) in driving lung inflammation such as asthma; however, the mechanisms controlling this pro-inflammatory function are not well understood. In particular, although dysregulation in cellular metabolism has been associated with severity of multiple lung diseases, whether specific metabolic factors influence ILC2 metabolic programming and modulate ILC2 functionality to drive inflammatory disease has never been examined. The central focus of this proposal is to understand how cell-intrinsic metabolic factors control ILC2 function to regulate development of lung inflammation. In new preliminary studies, I found that ILC2s were the dominant source of the amino acid enzyme Arginase 1 (Arg1), and that deletion of ILC2- intrinsic Arg1 dampened ILC2 responses and prevented lung inflammation. Furthermore, Arg1 was required for ILC2 polyamine generation and glucose metabolism, suggesting that Arg1 broadly alters the bioenergetic programming of ILC2s and that these metabolic changes may underlie the ability of ILC2s to drive lung inflammation. Despite these advances, fundamental gaps remain regarding the upstream regulatory signals required for ILC2 expression of Arg1 and the downstream metabolic mechanisms by which Arg1 influences ILC2 bioenergetic programming and effector function to drive lung inflammation. Using cutting-edge techniques in metabolic profiling and immunobiology, in this proposal I will dissect the ILC2-Arg1-dependent mechanisms regulating lung tissue inflammation by investigating (1) How transcriptional control of Arg1 affects ILC2 metabolic function and (2) how Arg1-derived polyamines regulate ILC2 bioenergetics to control lung inflammation. Greater understanding of the signals and mechanisms by which ILC2s drive lung inflammation may lead to improved, selective therapies blocking their function to ameliorate lung disease.
Chronic inflammatory diseases of the lung such as asthma are a major public health and economic concern worldwide and greater understanding of the mechanisms that regulate lung inflammation is needed in order to direct the development of novel, more selective therapeutic strategies. Recent studies have demonstrated the importance of immune cells called Group 2 innate lymphoid cells (ILC2s) in driving lung inflammation; however, the mechanisms controlling this pro-inflammatory function are not well understood. The central focus of this proposal is to understand how cell-intrinsic metabolic factors regulate ILC2 bioenergetic programming to control their ability to cause lung inflammation.
|Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061|
|Joseph, Ann M; Monticelli, Laurel A; Sonnenberg, Gregory F (2018) Metabolic regulation of innate and adaptive lymphocyte effector responses. Immunol Rev 286:137-147|