Neutrophil migration and inflammation

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Inflammation presents as swelling, redness, heat, and lost-of-function and is essential for the restoration of tissue homeostasis after injury and infection. Neutrophils are the major effector cells of acute inflammation that combat infection, promote wound healing and resolution of inflammation, while contributing to collateral tissue injury. In addition, neutrophils are exploited as vehicles that cross tissue barriers to deliver cargos to inflammation sites. A better understanding of the neutrophil-intrinsic mechanisms that regulate neutrophil migration will have broad translational importance in the prevention and treatment of a wide range of inflammation-related diseases. The challenges associated with studying neutrophils are a limited set of genetic tools and the plasticity of the cells in vivo. To address these challenges, the PI uses zebrafish, a genetically tractable vertebrate model with a well-conserved innate immune system. Findings on neutrophil intrinsic genes that regulate neutrophil migration generated in the zebrafish model are then validated in primary human or murine neutrophils. MicroRNAs are small RNA molecules of 22-24 nt that regulate homeostasis in health and disease. MicroRNA “mimics” and “inhibitors” are emerging as next-generation therapeutics because of their ability to modulate a network of genes. In addition, microRNAs are being used as tools to discover novel regulators of biological processes. A critical gap remains understanding how microRNAs regulate neutrophil function: despite the prominent microRNA profiling studies in neutrophils and in various diseases, microRNA functional studies are scarce. The PI’s lab has been at the forefront of addressing this unmet need by characterizing microRNAs and their targets in neutrophil migration. Building on their recent progress, the first project is to continue charactering microRNAs in regulating neutrophil migration with two sub aims: (1.1) identify microRNA targets as novel regulators of neutrophil migration and inflammation, and (1.2) characterize how RORα regulates neutrophil migration. A separate project is to characterize mechanisms delineating the role of mitochondria in neutrophil migration. Mitochondria fission promotes migration in many cell types, including lymphocytes, presumably by increasing mitochondria localization and ATP production at sites of high energy demand. On contrary, neutrophils possess a highly fused mitochondrial network and primarily use glycolysis for ATP generation, suggesting additional roles of mitochondria outside the realm of ATP. Specifically, the PI seeks to (2.1) characterize how MFN2 regulates neutrophil migration. The hypothesis is that MFN2-mediated mitochondrial-ER contact regulates Rac activation and neutrophil adhesion and migration. The PI will continue to (2.2) identify additional mitochondrial related genes as novel regulators of neutrophil migration and inflammation. An increased understanding of neutrophil migration and inflammation will open multiple fronts in cell biology and immunology. Additionally, as a result of this work, previously underexplored therapeutic possibilities to treat inflammatory diseases will come to light.