Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B
Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska
Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska
View: Text | PDF
Research Article Immunology Pulmonology

Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B

Abstract

Mothers living near high-traffic roads before or during pregnancy are more likely to have children with asthma. Mechanisms are unknown. Using a mouse model, here we showed that maternal exposure to diesel exhaust particles (DEP) predisposed offspring to allergic airway disease (AAD, murine counterpart of human asthma) through programming of their NK cells; predisposition to AAD did not develop in DEP pups that lacked NK cells and was induced in normal pups receiving NK cells from WT DEP pups. DEP NK cells expressed GATA3 and cosecreted IL-13 and the killer protease granzyme B in response to allergen challenge. Extracellular granzyme B did not kill, but instead stimulated protease-activated receptor 2 (PAR2) to cooperate with IL-13 in the induction of IL-25 in airway epithelial cells. Through loss-of-function and reconstitution experiments in pups, we showed that NK cells and granzyme B were required for IL-25 induction and activation of the type 2 immune response and that IL-25 mediated NK cell effects on type 2 response and AAD. Finally, experiments using human cord blood and airway epithelial cells suggested that DEP might induce an identical pathway in humans. Collectively, we describe an NK cell–dependent endotype of AAD that emerged in early life as a result of maternal exposure to DEP.

Authors

Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska

×

Figure 4

The type 2 immune response and AAD are dependent on IL-25.

Options: View larger image (or click on image) Download as PowerPoint
The type 2 immune response and AAD are dependent on IL-25. (A and B) Con...
(A and B) Concentrations of IL-25, IL-33, and TSLP in lung homogenates (A, n = 10 [IL-25] or n = 9 [IL-33, TSLP]) and BAL fluid (B, n = 10) from PBS-PBS, DEP-PBS, PBS-OVA, and DEP-OVA pups. (C–P) Depletion of IL-25 (C–H), IL-33 (I–L), and TSLP (M–P) in DEP-OVA pups. Pups received an anti-cytokine (anti–IL-25/anti–IL-33/anti-TSLP) antibody or isotype control IgG before immunization and then before the first challenge with OVA and were analyzed 72 hours after the final challenge (diagram of experimental strategy in Supplemental Figure 4B). (C) Percentages of IL25R+ST2– ILC2s, IL25R+ST2+ ILC2s, and IL25R–ST2+ ILC2s in live lung cells. n = 6. (D) OVA-specific IgE in the serum. n = 9. (E, J, and N) Total lung resistance to methacholine (FlexiVent). n = 5–6. (F, K, and O) Leukocyte subset counts in BAL fluid. n = 5–6. (G, H, L, and P) Images of H&E-stained lung sections. Original magnification, ×100. (G) Peribronchial inflammation scores (G, L, and P), images of PAS-stained lung sections (H), and proportions of bronchial epithelial areas that are PAS (mucin)+ (H, L, and P). n = 8–9 (anti–IL-25); n = 5 (anti–IL-33 and anti-TSLP). (I and M) Concentrations of IL-33 (I) and TSLP (M) in BAL fluid. n = 5. Data are representative of 2 (A, B, E, and I–P) or 3 (C, D, and F–H) independent experiments and are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test (A and B); 2-tailed unpaired t test (C, D, F–I, K–M, O, P); and 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (E, J, and N).