Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.
In mice at steady state, embryonically derived tissue-resident alveolar macrophages (AMs) self-sustain over a lifetime and fulfill their homeostatic function of surfactant removal. Following various lung insults, including influenza A virus infection and bleomycin-induced lung fibrosis, these cells show only minimal transcriptional and functional changes, suggesting that resident AMs are terminally differentiated, highly specialized, and not very plastic.
In naïve mice, the contribution of monocyte-derived cells to AMs is negligible, but they become major components of the AM population post-lung insult. The functionality of recruited AMs can determine increased antibacterial protection, reduced asthma, and elevated lung fibrosis, depending on the specific initial insult studied.
When the newly recruited population of monocyte-derived AMs persist in the mouse lung, they start to resemble tissue-resident AMs, suggesting that the lung environment sends cues to shape their relatively non-inflammatory, immunosedated phenotype.
The high reactivity of recently recruited AMs might be best explained as a transcriptional and epigenetic legacy from their prior monocyte identity. Alternatively, training, acting through epigenetic and transcriptional reprogramming on hematopoietic stem cells or monocytes in the blood or in the lung, may imprint the high reactivity of recruited AMs.