Differential activation of NF-Κβ and HIF-1α between fetal liver-derived and myeloid-derived macrophages drives inflammatory differences following Mycobacterium abscessus infection.

Pulmonary infections caused by Mycobacterium abscessus (Mab), a rapidly growing nontuberculous mycobacterium (NTM), are rising in patients with preexisting lung disease. Unfortunately, the natural recalcitrance of Mab to antibiotics drives high rates of treatment failures. Understanding the initial host-pathogen interactions that result in Mab control or disease is critical to identify new therapeutic targets. Lung macrophages are the first immune cells that Mab encounters, yet how distinct macrophage subsets, including resident fetal liver-derived alveolar macrophages (AMs) and recruited myeloid-derived macrophages, differentially respond to and control Mab remains unknown. Using primary AMs or fetal-liver derived alveolar macrophages (FLAMs) as a model of AMs and bone marrow macrophages (BMDMs) as a model of recruited myeloid macrophages, we found distinct macrophage subsets that similarly control intracellular Mab in resting and interferon-gamma (IFNγ)-activated cells with similar levels of cell death. However, divergent inflammatory responses were observed with resting BMDMs robustly activating NF-κB-dependent proinflammatory cytokines, while FLAMs only transiently induced this key inflammatory signature. We further found that Mab-infected IFNγ activated FLAMs and did not robustly induce HIF1α, resulting in reduced Nos2 expression. Thus, differences in the activation of transcription factors in fetal liver- and myeloid-derived macrophages drives distinct host responses against the same Mab pathogen. Our results provide a new understanding of early interactions with Mab in the lungs and suggest differences that distinct macrophage subsets may contribute to susceptibility to Mab pulmonary disease.