AKT2 Regulates Pulmonary Inflammation and Fibrosis via Modulating Macrophage Activation

Abstract

Idiopathic pulmonary fibrosis (IPF) is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although AKT2-mediated signaling pathways modulate inflammatory responses, their role in IPF has not been defined. We report that AKT2 deficiency () protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to mice could restore pulmonary fibrosis. In response to IL-33 treatment, macrophages displayed decreased production of IL-13 and TGF-β1 and attenuated phosphorylation of FoxO3a compared with macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of AKT2 and FoxO3a was remarkably upregulated. Collectively, these results indicate that AKT2 modulates pulmonary fibrosis through inducing TGF-β1 and IL-13 production by macrophages, and inhibition of AKT2 may be a potential strategy for treating IPF.

Lanatoside C protects mice against bleomycin‐induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

“…BLM causes damage to the alveolar epithelial cells, leading to an interstitial inflammatory response within the first week after its administration. 19,30 However, we found there were few significant and pathological conditions. 32,33 One important downstream target protein is FoxO1, which can be deactivated through phosphorylation at its three putative phosphorylation sites for Akt.…”

“…Inflammatory responses are a critical mechanism for PF progression. BLM causes damage to the alveolar epithelial cells, leading to an interstitial inflammatory response within the first week after its administration . However, we found there were few significant changes in BLM‐induced inflammation after lanatoside C administration (Figure A‐D) and that the effect of lanatoside C in regulating the development of BLM‐induced PF is not through suppressing the inflammatory response.…”

“…17,18 To verify this hypothesis, we assessed the impact of lanatoside C in a BLM-induced mouse model of pulmonary fibrosis. 19 We found that treatment with lanatoside C protected mice against pulmonary F I G U R E 1 Lanatoside C attenuated pathological changes and reduced mortality in bleomycin-induced pulmonary fibrosis of mice. A, Chemical structure of lanatoside C (LanC).…”

“…To verify this hypothesis, we assessed the impact of lanatoside C in a BLM‐induced mouse model of pulmonary fibrosis . We found that treatment with lanatoside C protected mice against pulmonary fibrosis in a dose‐dependent manner and reduced fibroblast proliferation, differentiation and migration in lung tissue.…”

Forkhead transcription factor FOXO3a mediates interferon‐γ‐induced MHC II transcription in macrophages

“…17 Nie et al have demonstrated that FOXO3a represses interleukin-13 transcription in macrophages to protect against bleomycin-induced pulmonary inflammation and fibrosis. 18 In addition, it has been shown that FOXO3a is capable of inhibiting the NLRP3 inflammasome by potentiating the transcription of Bim in liver macrophages (Kupffer cells). 19 Recently, genome-wide meta-analysis indicates that interplay between FOXO3a and certain MHC II molecules (e.g.…”