Extracellular vesicles presenting “don’t eat me” signal limit the efferocytic capacity in lung fibrosis

Efferocytosis is essential for tissue homeostasis and resolution of inflammation, yet its direct contribution to resolve organ fibrosis remains poorly understood. In idiopathic pulmonary fibrosis, a progressive age-driven lung disease, we found profound suppression of efferocytosis coupled with robust production and release of extracellular vesicles presenting functional receptor CD47, a canonical “don’t eat me” mediator. Restoration of efferocytosis contributes to the natural resolution of fibrosis, which is accelerated by CD47 deficiency or alterations in macrophage metabolic responses. In turn, pharmacologic disruption of efferocytic receptors or signaling results in lung fibrosis development and its persistence. While sustained reduction of efferocytic capacity align with fibrosis persistence in aged mice, AMPK activation promotes fibrosis resolution via reducing inflammaging and CD47 bioavailability, thus restoring clearance of apoptotic fibroblast. Importantly, AMPK activation also reprograms macrophages engaging apoptotic fibroblasts toward a fibrosis pro-resolving phenotype by suppressing TGF-β1 and promoting secretion of pro-regenerative hepatocyte growth factor (HGF). Together, these findings link metabolism and immune efferocytic fitness in lung fibrosis resolution and suggest that an AMPK senomorphic pathway has broad therapeutic relevance for fibrotic diseases.