Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs vs. Mo-AMs) are essential to development of experimental lung fibrosis. However, whether Apolipoprotein E (ApoE), which is produced abundantly by Mo-AMs in the lung, plays a role in the pathogenesis is unclear. In this study, we found that pulmonary ApoE was almost exclusively produced by Mo-AMs in mice with bleomycin induced lung fibrosis. We showed although ApoE was not necessary for developing maximal fibrosis in bleomycin injured lung, it was required for the resolution of this pathology. We found that ApoE directly bound to Collagen I and mediated Collagen I phagocytosis in vitro and in vivo, and this process was dependent on low density lipoprotein receptor-related protein 1 (LPR1). Furthermore, interference of ApoE/LRP1 interaction impaired the resolution of lung fibrosis in bleomycin treated wild-type mice. In contrast, supplementation of ApoE promoted this process in ApoE–/– animals. In conclusion, Mo-AM derived ApoE is beneficial to the resolution of lung fibrosis, supporting the notion that Mo-AMs may have distinct functions in different phases of lung fibrogenesis. The findings also suggest a novel therapeutic target for treating lung fibrosis, to which effective remedies remain scarce.
Huachun Cui, Dingyuan Jiang, Sami Banerjee, Na Xie, Tejaswini Kulkarni, Rui-Ming Liu, Steven R. Duncan, Gang Liu