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 3

The type 2 immune response and AAD are driven by NK cells.

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The type 2 immune response and AAD are driven by NK cells. The type 2 im...
The type 2 immune response and AAD in Ncr1iCre/+R26DTA/+ and R26DTA/+ DEP-OVA pups (A–J), Ncr1iCre/+R26DTA/+ and R26DTA/+ DEP-OVA pups after injection of CD127– NK cells (from R26DTA/+ littermates) or PBS as in Supplemental Figure 3B (K–N), and WT DEP-OVA pups after injection of anti–asialo-GM1 or control sera as in Supplemental Figure 3C (O–Q). (A and B) Cytokines in lung homogenates (A, n = 12) and BAL fluid (B, n = 13–15). (C, E, F, and K) Cytokine+ CD4+ T cells (C, n = 6), IL25R+ST2–, IL25R+ST2+, and IL25R–ST2+ ILC2s (E, n = 6; K, n = 6–8) and cytokine+ ILC2s (F, n = 6) in live lung cells. (D) OVA-specific IgE in serum. n = 9. (G, L, and O) Total lung resistance to methacholine. n = 6 (G and L); n = 5 (O). (H, J, N, and Q) H&E- and PAS-stained lung sections, inflammation scores, and areas of PAS+ epithelium. Original magnification, ×100. n = 7 (H); n = 8 (J, N, and Q). (I, M, and P) Leukocyte subsets in the BAL fluid. n = 8 (I); n = 6–8 (M); and n = 6 (P). Data are representative of 2 (A and B) or 3 (C–Q) independent experiments and are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired t test for (A–F, H–J, P, and Q); 1-way ANOVA with Tukey’s post hoc test (K, M, and N); 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (G, L, O).