| Autor: |
Thomas SM; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI., Ankley LM; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI., Conner KN; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI., Rapp AW; Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH., McGee AP; Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH., LeSage F; Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH., Tanner CD; Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH., Vielma TE; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI., Scheeres EC; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI., Obar JJ; Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH., Olive AJ; Department of Microbiology, Genetics, and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI. |
| Abstrakt: |
Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFβ is an important regulator of AM differentiation and maintenance, but how TGFβ directly modulates the innate immune responses of AMs remains unclear. This shortcoming prevents effective targeting of AMs to improve lung function in health and disease. Here we leveraged an optimized ex vivo AM model system, fetal-liver derived alveolar-like macrophages (FLAMs), to dissect the role of TGFβ in AMs. Using transcriptional analysis, we first globally defined how TGFβ regulates gene expression of resting FLAMs. We found that TGFβ maintains the baseline metabolic state of AMs by driving lipid metabolism through oxidative phosphorylation and restricting inflammation. To better understand inflammatory regulation in FLAMs, we next directly tested how TGFβ alters the response to TLR2 agonists. While both TGFβ (+) and TGFβ (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGFβ-dependent manner. Surprisingly, mitochondrial antiviral signaling protein and the interferon regulator factors 3 and 7 were required for IFN production by TLR2 agonists. Together, these data suggest that TGFβ modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs. |
