Trained immunity and related memory responses in lung health and disease

Abstract

Immune memory has long been attributed to adaptive immunity, but trained immunity has broadened this view by showing that innate immune cells can retain altered function after prior stimulation and mount an enhanced response upon rechallenge. In the lung, prior local exposures can alter resident alveolar macrophages, whereas systemic immune stimulation can reprogramme bone-marrow progenitors and alter their myeloid output. Epithelial signals and alveolar-capillary barrier integrity help determine whether these changes protect tissue or promote injury. Reported metabolic pathways and chromatin features differ among cell types and experimental models; mTOR- and HIF-1α-mediated glycolysis and changes in H3K4me3 or H3K27ac can support altered innate responses. These responses may improve host defence or preserve tissue function without reducing pathogen burden, but can also contribute to barrier injury, chronic inflammation and fibrosis; in established tumours, ongoing local signals support immunosuppressive and angiogenic myeloid functions. We compare trained immunity in pulmonary myeloid cells, including trained alveolar macrophages, with other forms of alveolar macrophage memory, innate lymphoid memory-like responses and memory in pulmonary epithelial and stromal cells, and examine how these responses shape pulmonary infection, acute lung injury, chronic airway inflammation, pulmonary fibrosis and lung tumours.