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 10

DEP NK cells drive HDM-induced AAD.

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DEP NK cells drive HDM-induced AAD. (A–H) Model of early life HDM-induce...
(A–H) Model of early life HDM-induced AAD in the context of maternal exposure to DEP. Pups of DEP-exposed and PBS-exposed mothers received HDM intranasally on postnatal days 5 and 6 (immunization phase) and then on postnatal days 23, 24, and 25 (challenge phase). Pups were analyzed on postnatal day 28 (diagram of experimental strategy in Supplemental Figure 10). (I–O) Genetic depletion of NK cells in DEP-HDM pups. DEP Ncr1iCre/+R26DTA/+ and R26DTA/+ littermate pups were generated as in Figure 3, A–J. After birth, pups were immunized and challenged with HDM and analyzed 72 hours after challenge. (A) Percentages of IL-5+ and IL-13+ NK cells in live lung NK cells (after ex vivo stimulation with PMA/ionomycin). n = 6 per group. (B and I) Percentages of IL-5+ and IL-13+ CD4+ T cells in live lung cells. n = 6. (C and J) HDM-specific IgE in the serum. n = 9. (D and K) Percentages of IL25R+ST2– ILC2s, IL25R+ST2+ ILC2s, and IL25R–ST2+ ILC2s in live lung cells. n = 5 (D); n = 10 (K). (E and L) Percentages of IL-5+ and IL-13+ ILC2s in live lung cells. n = 6. (F and M) Total lung resistance to methacholine. n = 6. (G and N) Leukocyte subset counts in BAL fluid. n = 5 (G); n = 8 (N). (H and O) Peribronchial inflammation scores (left, n = 5) and proportions of bronchial epithelial areas that are PAS+ (right, n = 5). Data are representative of 2 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–E, G, and H); 2-tailed unpaired t test (I–L, N, and O); and 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (F and M).