| First Author | Thomas SM | Year | 2026 |
| Journal | J Immunol | Volume | 215 |
| Issue | 5 | PubMed ID | 42152611 |
| Mgi Jnum | J:388613 | Mgi Id | MGI:8345849 |
| Doi | 10.1093/jimmun/vkag090 | Citation | Thomas SM, et al. (2026) TGFbeta primes alveolar-like macrophages to induce type I IFN following TLR2 activation. J Immunol 215(5) |
| abstractText | Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFbeta is an important regulator of AM differentiation and maintenance, but how TGFbeta 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 TGFbeta in AMs. Using transcriptional analysis, we first globally defined how TGFbeta regulates gene expression of resting FLAMs. We found that TGFbeta 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 TGFbeta alters the response to TLR2 agonists. While both TGFbeta (+) and TGFbeta (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in TGFbeta (+) FLAMs and primary AMs. Surprisingly, mitochondrial antiviral signaling protein and the IFN regulator factors 3 and 7 were required for IFN production by TLR2 agonists and the IFN response was dependent on mitochondrial reactive oxygen species. Together, these data suggest that TGFbeta modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs. |
