TGF-β1 Limits the Onset of Innate Lung Inflammation by Promoting Mast Cell-Derived IL-6

TGF-beta 1 is an important suppressive mediator of inflammation, but it can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung, and TGF-beta 1 was suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury, we demonstrate that TGF-beta 1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-beta 1 does not directly regulate neutrophil apoptosis but instead functions through IL-6 to promote neutrophil clearance. rIL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in bronchoalveolar lavage fluid, while IL-6 increases rapidly following LPS-induced injury. Mast cells are a critical source of IL-6, because mast cell deficient mice exhibit increased neutrophil numbers that are reduced by reconstitution with wild-type, but not IL-6(-/-), mast cells. Although IL-6 diminishes neutrophilia in mast cell deficient mice, TGF-beta 1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-beta 1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.