Evidence for reprogramming of monocytes into reparative alveolar macrophages in vivo by targeting PDE4b

摘要

Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Alveolar macrophages (AM)), the predominant sentinel cell type in the airspace, die in massive numbers while fending off pathogens. Recent studies indicate that the AM) pool is replenished by airspace-recruited monocytes, but the mechanisms instructing the conversion of recruited monocytes into reparative AMc) remain elusive. Cyclic AMP (cAMP) is a vascular barrier protective and immunosuppres-sive second messenger in the lung. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address the impact of mechanisms determining cAMP levels in AM) and regulation of mobilization of the reparative AM)-pool. RNA-seq analysis of flow-sorted M identified phosphodies-terase 4b (PDE4b) as the top LPS-responsive cAMP-regulating gene. We observed that PDE4b expression markedly increased at the time of peak injury (4h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for the transcription of PDE4b in M. Inhibition of PDE4 activity at the time of peak injury, using intratracheal rolipram, increased cAMP levels, augmented the reparative AM pool, and resolved lung injury. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited PDE4b-sensitive monocytes as the source of reparative AM. Interestingly, adoptive transfer of rolipram-educated AM into injured mice resolved lung edema. We propose suppression of PDE4b as an effective approach to promote reparative AM generation from monocytes for lung repair.