TGF-β1 limits the onset of innate lung inflammation by promoting mast cell-derived IL-6

• 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: United States 01-06-2013
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - immunology; Female; Immunity, Innate; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Lipopolysaccharides - adverse effects; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Knockout; Neutrophil Infiltration - immunology; Neutrophils - drug effects; Neutrophils - immunology; Pneumonia - chemically induced; Pneumonia - immunology; Pneumonia - metabolism; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1203362

TGF-β1 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-β1 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-β1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-β1 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-β1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-β1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.