TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.

Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGFb is an important regulator of AM differentiation and maintenance but, how TGFb 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 TGFb in AMs. Using transcriptional analysis, we first globally defined how TGFb regulates gene expression of resting FLAMs. We found that TGFb 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 TGFb alters the response to TLR2 agonists. While both TGFb (+) and TGFb (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGFb-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 TGFb modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs.