METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway

Abstract

Hepatic fibrosis (HF) is caused by chronic hepatic injury and is characterized by hepatic stellate cells (HSCs) activation. Studies focusing on the function of exosomes derived from macrophages in HF progression are limited. This study aims to identify the roles of exosomal NEAT1 derived from macrophages on HF and the underlying mechanisms. Our studies showed that METTL3 targeted and enhanced NEAT1 expression in macrophages. Exosomal NEAT1 originating from LPS-treated macrophages promoted HSCs proliferation and migration, and induced the expression of fibrotic proteins including collagen I, α-SMA, and fibronectin. Macrophage exosomal NEAT1 contributed to HSCs activation by sponging miR-342. MiR-342 directly targeted Sp1 and suppressed its downstream TGF-β1/Smad signaling pathway, which eventually led to the inhibition of HSCs activation. Depletion of NEAT1 in the macrophage exosomes inhibited HF progression both in vitro and in vivo. Altogether, our study proved that silence of NEAT1 in the macrophage exosomes exerted protective roles against HF through the miR-342/Sp1/TGF-β1/Smad signaling pathway, suggesting a potential therapeutic target in HF treatment.

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

“…29,30 The mechanistic link between loss of lipids in HSCs and cell activation is not well understood, but is thought to involve remarkable influence of the molecular and cellular pathways in hepatic inflammatory microenvironment. [30][31][32] Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells, 33,34 including macrophages, 35,36 neutrophils, 37,38 platelets, 33,39 dendritic cells, 40 sinusoidal endothelial cells, 41,42 epithelial cells, 43 natural killer cells, 44,45 various T lymphocytes, 46,47 and B cells, 48,49 promotes or inhibits the activation of HSCs. For example, inflammation induced by liver injury triggers the recruitment of macrophages to the liver, where they produce cytokines and chemokines, such as TGF-β, platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-α), IL-1β, oncostatin M (OSM), chemokine ligand 3/5 (CCL3/5), directly inducing HSC activation, and subsequently forming a definitely complex activation network.…”

LncRNA NEAT1 in the pathogenesis of liver‐related diseases

“…17 Furthermore, in the lipopolysaccharide treated macrophages, exosomal NEAT1 has been identified as a key player in promoting the proliferation and migration of HSCs. 90 Additionally, it has been observed that exosomal NEAT1 induces the expression of fibrotic proteins such as collagen I, α-SMA, and fibronectin. 90 The activation of HSCs is facilitated by the interaction between macrophage-derived exosomal NEAT1 and miR-342, where NEAT1 acts as a sponge for miR-342 90 (Figure 2).…”

“…90 Additionally, it has been observed that exosomal NEAT1 induces the expression of fibrotic proteins such as collagen I, α-SMA, and fibronectin. 90 The activation of HSCs is facilitated by the interaction between macrophage-derived exosomal NEAT1 and miR-342, where NEAT1 acts as a sponge for miR-342 90 (Figure 2).…”

Glycyrrhizic acid improves tacrolimus‐induced renal injury by regulating autophagy

“…Immunohischemical staining for Collagen I was performed in renal tissues by using a rabbit anti-Collagen I monoclonal antibody (ab270993, Abcam, Cambridge, UK; 1:800) as described previously. 23 Immunohischemical staining for p62 was performed in renal tissues by using a rabbit anti-p62 monoclonal antibody (cat#: A19700; ABclonal Technology, Wuhan, China; 1:200). Light microscope was used to capture the images (Leica, Wetzlar, Germany).…”