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
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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

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Figure 9

Granzyme B is required for development of AAD in predisposed pups.

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Granzyme B is required for development of AAD in predisposed pups. (A–F)...
(A–F) Importance of systemic granzyme B. DEP-exposed Gzmb+/– females were mated with unexposed Gzmb+/– males to generate Gzmb–/– and Gzmb+/+ littermates. Pups were immunized, challenged with OVA, and analyzed 72 hours after challenge. (G–L) Importance of NK cell–expressed granzyme B. Ncr1iCre/+R26DTA/+ pups were transferred with Gzmb+/+ and Gzmb–/– NK cells. Donor and recipients were the same age and were born to DEP-exposed mothers. Cell transfer took place on day 22 as in Figure 3, K–N. Before cell transfer, on postnatal day 5, donor and prospective recipient pups were immunized with OVA/alum. After cell transfer, recipients were challenged with OVA on days 23 to 25 and analyzed on day 28 (diagram of experimental strategy in Supplemental Figure 9). (A and G) Concentration of IL-25 in BAL fluid. n = 6 mice per group. (B and H) Percentages of IL25R+ST2– ILC2s, IL25R+ST2+ ILC2s, and IL25R–ST2+ ILC2s in live lung cells. n = 6. (C and I) Total lung resistance to methacholine. n = 6. (D and J) Leukocyte subset counts in BAL fluid. n = 6. (E and K) Left: H&E-stained lung sections. Original magnification, ×100. Right: peribronchial inflammation scores. n = 7. (F and L) Left: PAS-stained lung sections. Original magnification, ×100. Right: proportions of bronchial epithelial cell areas that are PAS+. n = 7. (M) Flow cytometric detection of IL-25 in EpCAM+NK1.1– airway epithelial cells that were incubated with IL-13 ± NK cells from spleens of DEP-OVA Gzmb+/+ and Gzmb–/– pups. Histogram is representative of 3 independent cocultures. Data are representative of 3 independent experiments and are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired t test (A, B, D–H, and J–L); 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (C and I).