Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury

초록

Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with beta-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. beta-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with beta-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of beta-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders. Innate immune training triggers myeloid cell production and functional reprogramming. beta-glucan can induce immune training, which increases pulmonary neutrophil accumulation and then boosts efferocytosis by alveolar macrophages. Efferocytosis enhances trained immunity through resolvin D1 release, inducing sirtuin 1 expression in epithelial cells for improved damage resistance. beta-glucan training forms a link among neutrophils, macrophages, and epithelial cells, thereby preventing lung fibrosis.image

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