Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

Abstract

Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.

Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl4 Exposure in Mice

“…Here, we analysed whether Smad7 function in LysM-expressing myeloid cells influenced the induction of liver fibrosis in the model of chronic CCl 4 application. We previously established a myeloid-specific knock-down mouse line by crossing a LysM-Cre expressing line with a floxed Smad7 line, in which we confirmed the lack of Smad7 expression in splenic CD11b pos myeloid cells [ 16 ] and hepatic Kupffer cells ( Figure S1 ). After extensive analysis of various parameters in chronically CCl 4 -treated LysM-Cre pos x Smad7 Δ / Δ mice and their LysM-Cre neg Smad7 fl/fl littermate controls, our results indicated that liver fibrosis development did not depend on the presence of Smad7 in LysM-expressing cells.…”

“…Using a myeloid-specific, Cre-mediated, Smad7 knock-down mouse model, in which efficient knock-down of Smad7 mRNA in myeloid cells, including splenic CD11b pos cells (Endig et al) [ 16 ] and CD64 pos Clec2a pos hepatic Kupffer cells ( Figure S1 ) was present, we investigated the extent of liver injury, inflammatory cell infiltration and fibrosis development after chronic CCl 4 exposure. To this end, LysM-Cre pos Smad7 Δ / Δ and Smad7 fl/fl littermate controls were treated with corn oil as a control or with CCl 4 in corn oil for 6 weeks.…”

Investigation of the therapeutic effect of Shaoyao Gancao decoction on CCL4‐induced liver injury in rats by metabolomic analysis

“…First, animal models of liver injury are needed. There are lots of ways to build experimental liver injury animal models, among which CCL 4 is widely selected to induce liver injury (Clichici et al, 2015; Endig et al, 2019). In recent years, because of the advantages Chinese herbal medicines offer in treating liver injury, such as better efficacy and fewer side effects, many relevant studies have been initiated (Jiang, Qin, et al, 2017).…”

Plasma Kallikrein as a Modulator of Liver Injury/Remodeling

“…Different subsets of immune cells have been detected at the acute injury site. Genes for the adhesion G protein–coupled receptor E1 (Adgre1), a marker of macrophage, lymphocyte antigen 6 complex, locus C1 and G, Ly6c, and Ly6g (markers of monocyte and neutrophil presence) have been shown to increase their expression in acute liver injury and inflammation ( Mitchell et al, 2009 ; Endig et al, 2019 ). We assessed the possibility of the PKKS gene association to these immune cell recruiting genes.…”