Differential activation of NF-κB and HIF-1α between alveolar-like macrophages and myeloid-derived macrophages drive inflammatory differences following Mycobacterium abscessus infection.
Pulmonary infections caused by Mycobacterium abscessus (Mab), a rapidly growing nontuberculous mycobacterium (NTM), are on the rise in patients with chronic or acquired lung disease. In contrast to immunocompetent individuals, these patient cohorts exhibit abnormal pulmonary function that result from chronic inflammation and mucus build-up. Treatment regimens rely on multi-drug cocktails yet Mabs natural recalcitrance to common antibiotics extends treatment timelines and increases the frequency of treatment failures. Thus, it is important to understand the mechanisms by which immunocompetent individuals clear Mab with relative ease while susceptible individuals do not. In the lungs, macrophages are the first immune cell Mab encounters following infection, with both resident alveolar macrophages and recruited myeloid derived macrophages playing important roles during infection control. However, the specific role of these distinct macrophage populations in regulating control and inflammatory responses during Mab remains limited due to a lack of ex vivo models that recapitulate the functions of different macrophage subsets. Here, we leverage a fetal-liver derived alveolar macrophage (FLAM) model to define early inflammatory responses occurring at the Mab-macrophage interface compared to bone-marrow derived macrophages (BMDMs). Even though both FLAMs and BMDMs similarly control intracellular Mab, the inflammatory response between these macrophage populations is significantly different. BMDMs robustly activated NF-{kappa}B transcriptional targets that include important chemokines and inflammatory cytokines like TNF, FLAMs transiently induced these genes following Mab infection. While activation of FLAMs or BMDMs with IFN{gamma} prior to Mab infection did not alter Mab intracellular dynamics, it did drive FLAMs to be more inflammatory, yet important differences remained compared to BMDMs, including the lower expression of the inducible nitric oxide synthase. This was reversed with chemical activation of HIF1. We conclude that FLAMs and BMDMs differentially respond to Mab infection due to differences in signaling networks activated following innate immune sensing, with FLAMs being more hypoinflammatory than BMDMs. More broadly our results highlight a need to better understand the initial interactions with Mab and distinct macrophage populations to define pathways that contribute to pulmonary protection or disease.