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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL122995-06
Application #
9817614
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2015-01-01
Project End
2024-11-30
Budget Start
2020-02-01
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Liu, Sucai; Verma, Mukesh; Michalec, Lidia et al. (2018) Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin. J Allergy Clin Immunol 141:257-268.e6
Verma, Mukesh; Liu, Sucai; Michalec, Lidia et al. (2018) Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations. J Allergy Clin Immunol 142:793-803.e8
Gorska, Magdalena M (2018) Mouse Models of Asthma. Methods Mol Biol 1809:351-362
Lenberg, Jerica; Qian, Qian; Sun, Zehua et al. (2018) Pre-pregnancy exposure to diesel exhaust predisposes offspring to asthma through IL-1? and IL-17A. J Allergy Clin Immunol 141:1118-1122.e3
Gorska, Magdalena M (2017) Natural killer cells in asthma. Curr Opin Allergy Clin Immunol 17:50-54
Liu, Weimin; Liu, Sucai; Verma, Mukesh et al. (2017) Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol 139:1548-1558.e4
Christianson, Christina A; Goplen, Nicholas P; Zafar, Iram et al. (2015) Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol 136:59-68.e14
Manners, Sarah; Alam, Rafeul; Schwartz, David A et al. (2014) A mouse model links asthma susceptibility to prenatal exposure to diesel exhaust. J Allergy Clin Immunol 134:63-72