IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response

Abstract

The innate immune molecule surfactant protein-D (SP-D) plays an important regulatory role in the allergic airway response. In this study, we demonstrate that mice sensitized and challenged with either Aspergillus fumigatus (Af) or OVA have increased SP-D levels in their lung. SP-D mRNA and protein levels in the lung also increased in response to either rIL-4 or rIL-13 treatment. Type II alveolar epithelial cell expression of IL-4Rs in mice sensitized and challenged with Af, and in vitro induction of SP-D mRNA and protein by IL-4 and IL-13, but not IFN-γ, suggested a direct role of IL-4R-mediated events. The regulatory function of IL-4 and IL-13 was further supported in STAT-6-deficient mice as well as in IL-4/IL-13 double knockout mice that failed to increase SP-D production upon allergen challenge. Interestingly, addition of rSP-D significantly inhibited Af-driven Th2 cell activation in vitro whereas mice lacking SP-D had increased numbers of CD4+ cells with elevated IL-13 and thymus- and activation-regulated chemokine levels in the lung and showed exaggerated production of IgE and IgG1 following allergic sensitization. We propose that allergen exposure induces elevation in SP-D protein levels in an IL-4/IL-13-dependent manner, which in turn, prevents further activation of sensitized T cells. This negative feedback regulatory circuit could be essential in protecting the airways from inflammatory damage after allergen inhalation.

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice

“…46 We have previously shown that the lung collectin SP-D has immunosuppressive activities 15 and that it protects against inflammatory changes of the lung. 40 In this study we investigated the regulatory link between these innate immune molecules.…”

“…[16][17][18][19] Our previous studies in SP-D −/− mice also demonstrated the presence of activated CD3/CD4 + T cells in the airway submucosal tissue with strikingly increased levels of thymus and activation-regulated chemokine, a chemokine responsible for attracting T H 2 and dendritic cells. 15 These findings suggested that in addition to macrophages, dendritic cells also might be affected by a lack of SP-D and that this lung collectin might have an essential role in maintaining immune homeostasis in the lung under normal, noninflammatory circumstances.…”

“…5 Compelling evidence was provided to support the importance of SP-A and SP-D in innate immune function by studies on gene-deficient mice. Animals lacking either lung collectins have shown an increased susceptibility to bacterial, 6-8 viral, [9][10][11] fungal, 12 endotoxin, 13 and allergen-induced 14,15 lung inflammation. Under normal conditions, however, SP-A −/− mice display no pathologic features in the lung.…”

“…For the in vitro type II cell culture studies, adult (200 g) Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) were used, as previously described. 15,39 BALB/c mice were sensitized and challenged with Aspergillus fumigatus, as described previously, 38 and studied 0 (not challenged), 1, 6, 12, 24, 48, and 72 hours later. In brief, mice were sensitized intraperitoneally with 20 μg of A fumigatus (Hollister-Stier, Spokane, Wash) together with 20 mg of alum (Imject Alum; Pierce, Rockford, Ill) in 100 μL of PBS at days 0 and 14, followed by intranasal challenge on day 28 with 25 μL of A fumigatus extract in glycerol-PBS.…”

“…15,41,42 To dissect the pathologic events characterizing the onset and resolution of the inflammatory airway response, separate groups of animals were investigated 1, 12, 24, 48, and 72 hours after allergen challenge, and sensitized but nonchallenged (0 hour) and naive mice were used as control animals. There was a significant influx of mononuclear cells into the airways very early, 1 hour after allergen challenge of sensitized mice.…”