TGFβ1 limits the onset of innate lung inflammation by promoting mast cell-derived IL-61

• Published in: The Journal of immunology (1950) Vol. 190; no. 11; pp. 5731 - 5738
• Main Authors: Ganeshan, Kirthana, Johnston, Laura K., Bryce, Paul J.
• Format: Journal Article
• Language: English
• Published: 29-04-2013
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1203362

TGFβ1 is an important suppressive mediator of inflammation but can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung and TGFβ1 has been suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury (ALI), we demonstrate that TGFβ1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis, rather than less migration. We demonstrate that TGFβ1 does not directly regulate neutrophil apoptosis, but instead functions through IL-6 to promote neutrophil clearance. Recombinant IL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in brochoalveolar lavage fluid while IL-6 is rapidly elevated following LPS-induced injury. Mast cells are a critical source of the IL-6, as mast cell deficient mice exhibit increased neutrophil numbers that is reduced by reconstitution with WT, but not IL-6
−/−
, mast cells. While IL-6 diminishes neutrophilia in mast cell-deficient mice, TGFβ1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGFβ1, likely derived from resident Tregs, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.