Many studies have reported genetic associations between IL-33, its receptor IL1RL1 (ST2), and asthma. However, the cellular sources of IL-33 and the mechanisms by which it promotes Th2 pulmonary inflammation are poorly understood. We and others have shown that IL-33 is elicited by house dust mite (HDM) activation of the C-type lectin receptor Dectin-2 in dendritic cells (DCs). Therefore, we sought to determine the contribution of IL-33 and IL1RL1 to DC-mediated allergic pulmonary inflammation.
C57BL/6 WT, Il33‒/‒ and Il1rl1‒/‒ bone marrow-derived DCs (BMDCs) were stimulated with PBS or HDM extract. Culture supernatants were analyzed for cytokines by ELISA. 104 PBS- or HDM-pulsed BMDCs were administered intranasally to sensitize WT recipients (day 0). Recipients were challenged with 3 μg HDM on days 11 and 13, and BAL fluid cellular infiltrate was evaluated on day 15.
WT mice sensitized with HDM-pulsed Il1rl1‒/‒ BMDCs had a marked reduction in BAL inflammation, including neutrophilia, as compared to mice sensitized with HDM-pulsed WT BMDCs. In contrast, mice sensitized with HDM-pulsed Il33‒/‒ BMDCs had a significant enhancement in BAL inflammation, especially neutrophils. Analysis of the culture supernatants from HDM-pulsed Il33‒/‒ BMDCs revealed enhanced generation of NF-κB-dependent cytokines, such as IL-23 and TNF-α, as compared to HDM-pulsed WT or Il1rl1‒/‒ BMDCs.
IL-33 elicited in HDM-pulsed DCs reduces allergic pulmonary inflammation. These findings suggest that, in addition to its role as a pro-inflammatory cytokine extracellularly, IL-33 can inhibit NF-κB-dependent gene expression intracellularly and negatively regulate innate immune cell function.