Infection with the parasitic helminth Schistosoma mansoni causes significant liver fibrosis and extracellular matrix (ECM) remodeling. Matrix metalloproteinases (MMP) are important regulators of the ECM by regulating cellular inflammation, extracellular matrix deposition, and tissue reorganization. MMP12 is a macrophage-secreted elastase that is highly induced in the liver and lung in response to S. mansoni eggs, confirmed by both DNA microarray and real-time PCR analysis. However, the function of MMP12 in chronic helminth-induced inflammation and fibrosis is unclear. In this study, we reveal that MMP12 acts as a potent inducer of inflammation and fibrosis after infection with the helminth parasite S. mansoni. Surprisingly, the reduction in liver and lung fibrosis in MMP12-deficient mice was not associated with significant changes in cytokine, chemokine, TGF-β1, or tissue inhibitors of matrix metalloproteinase expression. Instead, we observed marked increases in MMP2 and MMP13 expression, suggesting that Mmp12 was promoting fibrosis by limiting the expression of specific ECM-degrading MMPs. Interestingly, like MMP12, MMP13 expression was highly dependent on IL-13 and type II–IL-4 receptor signaling. However, in contrast to MMP12, expression of MMP13 was significantly suppressed by the endogenous IL-13 decoy receptor, IL-13Rα2. In the absence of MMP12, expression of IL-13Rα2 was significantly reduced, providing a possible explanation for the increased IL-13-driven MMP13 activity and reduced fibrosis. As such, these data suggest important counter-regulatory roles between MMP12 and ECM-degrading enzymes like MMP2, MMP9, and MMP13 in Th2 cytokine-driven fibrosis.

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Background Atopic dermatitis (AD) is common in children; however, persistence of AD with or without asthma, is less common. Longitudinal studies remain limited in their ability to characterize how IgE antibody responses evolve in AD, and their relationship to asthma. Objective To use a cross-sectional study design of children with active AD to analyze age-related differences in IgE antibodies and relation to wheeze. Methods IgE antibodies to food and inhalant allergens were measured in children with active AD (5 months to 15 years of age, n=66), with and without history of wheeze. Results Whereas IgE antibodies to foods persisted at a similar prevalence and titer throughout childhood, IgE antibodies to all aeroallergens rose sharply into adolescence. From birth, the chance of sensitization for any aeroallergen increased for each 12-month increment in age (OR≥1.21, p≤0.01), with the largest effect observed for dust mite (OR=1.56, p<0.001). A steeper age-related rise in IgE antibody titer to dust mite, but no other allergen, was associated with more severe disease. Despite this, sensitization to cat was more strongly associated with wheeze (OR=4.5, p<0.01), and linked to Fel d 1 and Fel d 4, but not Fel d 2. Comparison of cat allergic children with AD to those without, revealed higher titers to Fel d 2 and Fel d 4 (p<0.05), but not Fel d 1. Conclusions and Clinical Relevance Differences in sensitization to cat and dust mite among young children with AD may aid in identifying those at increased risk for disease progression and development of asthma. Early sensitization to cat and risk for wheeze among children with AD may be linked to an increased risk for sensitization to a broader spectrum of allergen components from early life. Collectively, our findings argue for early intervention strategies designed to mitigate skin inflammation in children with AD.

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