Immunomodulatory role of IL-37 in asthma pathogenesis

Introduction: Impaired production of interleukin (IL) 37 in allergic asthmatics suggests a role for IL-37 in asthma pathogenesis. We have previously shown that IL-37 ameliorates experimental asthma via a mechanism that requires IL-18 recector (R) α and single Ig IL-1-related receptor (SIGIRR). Aims and objectives: We aim to further clarify, how the anti-inflammatory effect of IL-37 on asthma pathogenesis is mediated. Methods: IL-18Rβ- and IL-18 binding protein (BP)-deficient with acute experimental asthma mice were treated with IL-37. Airway inflammation, mucus production and airway hyperresponsiveness (AHR) were compared to an untreated and a healthy control group. Expression of IL-18Rα and SIGIRR was analyzed in different cells and tissues. Production of T helper 2 (Th2) cytokines in mononuclear cells (MNC) was assessed by cytometric bead array. Results: IL-37 ameliorated experimental asthma in IL-18Rβ- as well as in IL-18BP-deficient mice by points of airway inflammation, mucus production and AHR, which was comparable to the effects in wildtype animals. IL-18Rα and SIGIRR were expressed by airway epithelial cells (AEC), smooth muscle cells (SM cells), dendritic cells (DC) and T cells. IL-37 reduced the production of Th2 cytokines within MNC. Conclusion: IL-37 diminished allergic airway inflammation via a mechanism that did neither require IL-18Rβ nor IL-18BP. This demonstrates that IL-37 does not simply inhibit the pro-inflammatory IL-18 signal via a SIGIRR-mediated blockade of the IL-18R formation or a IL-18BP mediated neutralization of IL-18. AEC, DC and T cells expressed IL-18Rα and SIGIRR and therefore represent potential target cells for IL-37. In vitro IL-37 diminished Th2 cell functions.