Abstract
Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs and Mo-AMs, respectively) that 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 that, 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 WT 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 potentially novel therapeutic target for treating lung fibrosis, to which effective remedies remain scarce.
Highlights
Pulmonary fibrosis is typically characterized by progressive and irreversible lung scarring, which eventually leads to respiratory failure and death [1]
We showed that apolipoprotein E (ApoE), a key molecule involved in lipid metabolism [21], was produced primarily by Mo-Alveolar macrophages (AMs) during bleomycin lung injury
Upon survey of the transcriptomes of monocyte-derived AMs (Mo-AMs) and tissue-resident AMs (TR-AMs) from mice that were treated intratracheally (i.t.) with bleomycin, we were interested in ApoE because (a) it is one of the most differentially expressed genes in Mo-AMs as compared with TR-AMs from bleomycin-treated lungs and (b) its abundance in Mo-AMs is much greater than several previously defined profibrotic mediators in this AM subtype, such as PDGF and Collagen VI [10, 23, 24]
Summary
Pulmonary fibrosis is typically characterized by progressive and irreversible lung scarring, which eventually leads to respiratory failure and death [1]. Alveolar macrophages (AMs) have long been known to play a crucial role in the development of lung fibrosis by differentiating into a profibrotic M2 phenotype, a mechanism that was well received in the past [4,5,6,7]. This paradigm is conceptually imprecise because of lacking consideration of the AM heterogeneity present during lung injury and repair [8]. While ApoE did not play a role in developing the maximal fibrosis in bleomycin-treated lung, it was indispensable to the resolution of this pathology. Our data reveal that a previously unappreciated role of the monocyte-derived subset of AMs may not just passively respond with phenotype change during injury, but they actively participate in resolving fibrosis and maintaining lung homeostasis
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