Efferocytosis of apoptotic alveolar epithelial cells is sufficient to initiate lung fibrosis

Abstract

Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic lung diseases and animal models of pulmonary fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in lung fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces lung fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.

Human menstrual blood-derived stem cells mitigate bleomycin-induced pulmonary fibrosis through anti-apoptosis and anti-inflammatory effects

“…Mounting evidence has shown that the apoptosis of type II alveolar epithelial cells leads to persistent and excessive migration and activation of fibroblast in the lung interstitium, leading to subsequent generation and accumulates myofibroblasts, which is closely associated with the progression of pulmonary fibrosis. It is likely that loss of the anti-fibrotic characteristics of intact epithelial cells and the increasing secretion of profibrotic factors from injured epithelial cells causes fibrosis [ 42 ]. In the present study, we also found that MenSCs can alleviate BLM-induced apoptosis of MLE-12 cells in vitro.…”

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

“…Instillation of Ox-PC directly into the mouse lung induced foam cell formation and accumulation and development of PF. The increased accumulation of lipids in macrophages occurs through efferocytosis whereby macrophages engulf apoptotic alveolar type II epithelial cells after injury via CD36 on the macrophages [319][320][321]. Targeted deletion of the lipid efflux transporter, ATP-binding cassette sub-family G member 1 (Abcg1) increased foam cell formation and exacerbated lung fibrosis in mice from bleomycin challenge [320].…”

“…The increased accumulation of lipids in macrophages occurs through efferocytosis whereby macrophages engulf apoptotic alveolar type II epithelial cells after injury via CD36 on the macrophages [319][320][321]. Targeted deletion of the lipid efflux transporter, ATP-binding cassette sub-family G member 1 (Abcg1) increased foam cell formation and exacerbated lung fibrosis in mice from bleomycin challenge [320]. Thus, a pneumocytes-macrophage-CD36-oxidized lipid signaling axis has been proposed to play a key role in the development of lung fibrosis in the bleomycin model [319,322].…”

Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

“…Regarding the pathology of fibrosis, phagocytosis of apoptotic cells was reported to induce the production of pro-fibrotic cytokines, such as TGF-β, by macrophages [40][41][42]. TGF-β has been regarded as a key molecule for fibrosis regulation, and further induces the expression of connective tissue growth factor (CTGF) through a functional Smad3-binding site in the CTGF promoter [43].…”