A growing number of epidemiological studies link childhood asthma with maternal environmental exposures with the strongest evidence provided for cigarette smoke and diesel exhaust. Mechanisms how maternal exposures lead to asthma in offspring are unknown. To address this, we developed a mouse model, inducing asthma susceptibility in young mice by exposing their mothers to diesel exhaust particles (DEP). We then discovered that asthma in this model was driven in part by natural killer (NK) cells. This finding was surprising because it did not fit into the traditional paradigm of NK cells serving as a body?s defense instrument designed to KILL. Our new data indicate, that instead, NK cells are part of a homeostatic response to REPAIR (NOT kill) fetal tissues that are metabolically-impaired by diesel exhaust, and that metabolic impairment is the primordial cause of asthma predisposition in our model. Metabolic impairment of DEP pups manifests itself in their reduced weight. The body?s first response to growth-limiting insults is induction of pro-survival factors. Accordingly, hematopoietic tissues of DEP fetuses and pups over-produce growth arrest-specific protein 6 (Gas6), a cytokine known to be induced under conditions of reduced metabolism and impaired growth to protect tissues from death and promote their repair. Tissue repair has long been linked to type-2 immune responses. Consistent with this, injections of Gas6 promote type-2 innate lymphoid cell (ILC2) activation and asthma in normal pups. We hypothesize that Gas6 effects are at least in part due to induction of a type-2 program in developing NK cells, and that this program endows NK cells with a capacity to orchestrate responses of type-2 lymphocytes. Gas6 is a recognized enhancer of NK cell development. It is also a known activator of STAT6, a transcriptional factor linked to type-2 differentiation. Accordingly, NK cell development is enhanced in DEP offspring and their mature NK cells produce the type-2 cytokine IL13. We further show that in DEP pups, NK cells drive production of epithelial IL25 and activation of ILC2 and Th2 cells. In addition to producing IL13, DEP NK cells have enhanced ability to degranulate. We propose that these two traits underlie the unique capacity of DEP NK cells to activate type-2 immunity. We show that the granule protease granzyme B (Gzmb) potently synergizes with IL13 to induce IL25 from airway epithelial cells. Our overarching hypothesis is that maternal exposure to DEP promotes asthma susceptibility in offspring by impairing their metabolism and growth; this provokes a repair response, part of which is induction of Gas6 that programs NK cells for enhanced secretion of IL13 and granzyme B, leading to production of IL25 and activation of ILC2 and Th2 cells.
In Aim 1, we will study NK cell-driven mechanisms of prenatally-programmed asthma, focusing on NK cell mediators (Gzmb and IL13) and IL25.
In Aim 2, we will study importance of Gas6 in NK cell programming and transmission of asthma susceptibility.
In Aim 3, we will use human blood samples to test a hypothesis that over-activation of the Gas6 pathway in NK cells in early childhood is a predictor of future asthma.
If successful, this project will define new mechanisms linking maternal exposure to diesel exhaust with predisposition to asthma in offspring, reveal putative therapeutic targets to prevent asthma and identify novel early biomarkers of asthma risk.
