Adenovirus‑mediated knockdown of activin A receptor type�2A attenuates immune‑induced hepatic fibrosis in mice and inhibits interleukin‑17‑induced activation of primary hepatic stellate cells

Abstract

Fibrosis induces a progressive loss of liver function, thus leading to organ failure. Activins are secreted proteins that belong to the transforming growth factor (TGF)-β superfamily, which initiate signaling by binding to their two type II receptors: Activin A receptor type 2A (ACVR2A) and activin A receptor type 2B. Previous studies that have explored the mechanisms underlying immune-induced hepatic fibrosis have mainly focused on TGF-β signaling, not activin signaling. To investigate the role of the activin pathway in this disease, adenovirus particles containing short hairpin (sh)RNA targeting ACVR2A mRNA (Ad-ACVR2A shRNA) were administered to mice, which were chronically treated with concanavalin A (Con A). The pathological changes in the liver were evaluated with hematoxylin/eosin staining, Masson trichrome staining and immunohistochemical assay. The results detected an increase in serum activin A and liver ACVR2A in Con A-treated animals. Conversely, liver function was partially restored and fibrotic injury was attenuated when activin signaling was blocked. In addition, the activation of hepatic stellate cells (HSCs) in response to Con A was suppressed by Ad-ACVR2A shRNA, as evidenced by decreased α-smooth muscle actin, and type I and IV collagen expression. Furthermore, primary mouse HSCs (mHSCs) were activated when exposed to interleukin (IL)-17A or IL-17F, which are two major cytokines produced by cluster of differentiation 4+ T helper 17 cells. The levels of activin A, type I and IV collagen were determined with ELISA kits and the expression of fibrotic molecules was determined with western blot analysis. Conversely, blocking activin/ACVR2A impaired the potency of HSCs to produce collagens in response to IL-17s. In addition, C terminus phosphorylation of Smad2 on Ser465 and Ser467, induced by either Con A in the liver or by IL-17s in mHSCs, was partly inhibited when activin A/ACVR2A signaling was suppressed. Collectively, the present study demonstrated an involvement of activated activin A/ACVR2A/Smad2 signaling in immune-induced hepatic fibrosis.

Activin A as a Novel Chemokine Induces Migration of L929 Fibroblasts by ERK Signaling in Microfluidic Devices

“…As suggested in previous studies, activin A controls the cytokine signaling cascades that drive the inflammatory response (Jones et al, 2007), and regulate the activation of M2 macrophages to affect tissue healing and fibrosis in the late stage of inflammation (Morianos et al, 2019). Furthermore, as an important factor in inducing liver, kidney and lung fibrosis, activin A is reported to be tightly associated with the occurrence and development of numerous fibrotic diseases (Hardy et al, 2015;Hruska et al, 2017;Zhang et al, 2018).…”

3D biomimetic tumor microenvironment of HCC to visualize the intercellular crosstalk between hepatocytes, hepatic stellate cells, and cancer cells

“…α-SMA is a known molecular marker for activated HSCs. [20] We con rmed by RT-qPCR that when LX2 is cultured alone or co-cultured with 7702, the expression of α-SMA was low or not detected. However, when HCC cells were present in the co-culture system, α-SMA was in high gene expression.…”

Antagonistic effects of activin A and TNF-α on the activation of L929 fibroblast cells via Smad3-independent signaling

“…Activin A expression is up-regulated www.nature.com/scientificreports/ in the pathological process of various tissue damage and inflammation 19,20 . In addition, activin A is one of the vital cytokines that cause liver, kidney and lung fibrosis [21][22][23] .…”