IL-33 is a tissue-derived cytokine that is abundantly expressed in the human lung, where it is involved in pathogen defense and barrier homeostasis. IL-33 alerts immune cells during allergen exposure and drives the downstream production of Th2 responses. Notably, while IL-33 has long been implicated in asthma, the sources of the cytokine have remained controversial. Here, we probed the cellular sources of human IL33 using human donor lungs and show that basal cells and endothelial cells are the dominant producers. In stark contrast, murine Il33 was found almost exclusively in lung epithelial type II pneumocytes. Further, the SNP-containing regulatory components in the human IL33 locus are not conserved in the murine locus. Given these differences, we engineered a novel IL33 reporter mouse containing the regulatory components from the human locus to reflect human IL33 expression in a murine model. We show that the human IL33 reporter is dramatically reduced by allergic inflammation and by direct administration of recombinant IL-33 in vivo, whereas IL33 reporter expression was unaltered airway epithelium. Extracellular IL-33 negatively regulated intracellular IL33 levels by inducing mRNA instability in endothelium, suggesting a mechanism for how IL-33 is able to dampen its inflammatory effects. Together, these data reveal a previously unrecognized cellular network comprised of crosstalk between the lung vasculature and the immune system that maintains tissue homeostasis and governs responses in allergic airway disease in humans.




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