Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B
Qian Qian, … , Eric Vivier, Magdalena M. Gorska
Qian Qian, … , Eric Vivier, Magdalena M. Gorska
Published May 14, 2020
Citation Information: J Clin Invest. 2020;130(8):4133-4151. https://doi.org/10.1172/JCI130324.
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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 1

Maternal exposure to DEP enhances type 2 immune response and AAD in offspring.

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Maternal exposure to DEP enhances type 2 immune response and AAD in offs...
(A–J) AAD and type 2 immune response in lungs of PBS-PBS, DEP-PBS, PBS-OVA, and DEP-OVA pups. (A) Total lung resistance to methacholine in indicated groups of pups. n = 6. Rrs, resistance of the respiratory system. (B) Leukocyte subsets in BAL fluid. n = 6. (C) Peribronchial inflammation scores (left) and proportions of bronchial epithelial (epi) areas that are PAS (mucin)+ (right). n = 6. (D) Flow cytometry (FC) plots to quantify pulmonary IL-5+ and IL-13+ CD4+ T cells. PMA/ionomycin-stimulated lung cell suspensions were stained for flow cytometry. After ex vivo stimulation with PMA/Ionomycin, staining, exclusion of debris, doublets, and dead cells, live (eFluor506–) lung singlets were gated on CD3+CD4+ cells and then on cytokine+ cells. (E) Percentages of cytokine+ CD4+ T cells in live lung cells. n = 6. (F) OVA-specific IgE in serum. n = 9. (G) FC plots to quantify lung ILC2 subsets. Live lung singlets (no ex vivo stimulation) were analyzed for Lineage/Lin markers (CD3, B220, CD11b, CD11c, Gr1, FcεRIα, and NK1.1) and CD45. CD45+Lin– cells were analyzed for CD127. CD127+ cells were analyzed for IL25R and ST2 to quantify IL25R+ST2–, IL25R+ST2+, and IL25R–ST2+ ILC2 subsets (CD45+Lin–CD127+IL25R+ST2–, CD45+Lin–CD127+IL25R+ST2+, and CD45+Lin–CD127+IL25R–ST2+ cells, respectively). (H) Percentages of ILC2 subsets in live lung cells. n = 6. (I) Gating strategy to quantify pulmonary cytokine+ ILC2s. PMA/ionomycin-stimulated live singlets were gated on CD45+Lin– cells, then on CD127+ cells and finally on cytokine+ cells. (J) Percentages of cytokine+ ILC2s in live lung cells. n = 6. Data are representative of 3 independent experiments and are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (A); 1-way ANOVA with Tukey’s post hoc test (B, C, E, F, H, and J).