Blockade of lncRNA‐ASLNCS5088–enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation

Abstract

In hypertrophic scar (HS) formation, the type 2 immune response induces the alternatively activated macrophages (M2), which manipulate fibroblasts to differentiate into myofibroblasts with active biologic functions and proliferation. Myofibroblasts express α‐smooth muscle actin (α‐SMA) and synthesize and produce additional collagen type I and collagen type III, inducing HS formation. However, studies on the mechanism of M2 macrophage modulation are only based on the recognition of profibrotic factors such as TGF‐β1 secreted by macrophages. The influence of exosomes from M2 macrophages on scar formation is still unknown. Both M2 macrophages and myofibroblasts highly express glutaminases (GLSs). GLS is a critical enzyme in glutaminolysis and is important for M2 macrophage and fibroblast polarization. In this study, we found that in a TGF‐β1‐stimulated coculture system, a long noncoding RNA (lncRNA) named lncRNA‐ASLNCS5088 was enriched in M2 macrophage‐derived exosomes. This lncRNA could be transferred with high efficiency to fibroblasts and acted as an endogenous sponge to adsorb microRNA‐200c‐3p, resulting in increased GLS and α‐SMA expression. Pretreatment with GW4869, which impairs M2 macrophage exosome synthesis, ameliorated these pathologic changes in fibroblasts in vitro. Local injection in the late scar formation period with GW4869 reduced α‐SMA+ fibroblasts and alleviated the fibrosis of tissue after wound healing in vivo.—Chen, J., Zhou, R., Liang, Y., Fu, X., Wang, D., Wang, C. Blockade of lncRNA‐ASLNCS5088–enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 33, 12200–12212 (2019). http://www.fasebj.org

RETRACTED: Mechanisms of M2 Macrophage-Derived Exosomal Long Non-coding RNA PVT1 in Regulating Th17 Cell Response in Experimental Autoimmune Encephalomyelitisa

“…It is believed that M2 macrophage-derived exosomes (M2-exos) transfer certain proteins or signals to tumor cells to regulate their migration (10). Specific long non-coding RNAs (lncRNAs) are preferentially packaged into exosomes, and the abundance of exosomal lncRNA correlates with their expression in the original cells (11). The lncRNA plasmacytoma variant translocation 1 (PVT1), located at 8q24.21, is recognized as an oncogene in diverse cancers, whose aberrant expression is proven to relate to cancer development (12).…”

Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases

“…EVs from macrophages exposed to silica also up-regulate α-SMA expression in fibroblasts due to the abundant miR-125a-5p in these EVs 104 . Moreover, EVs from M2-like macrophages are enriched with miR-328 and lncRNA-ASLNCS5088, which subsequently activates TGF-β and profibrotic factors (e.g., α-SMA, Collagen I) in fibroblasts 105 , 106 .…”

LncRNA MM2P-induced, exosome-mediated transfer of Sox9 from monocyte-derived cells modulates primary chondrocytes

“…2e and 3c-g). Recent studies have revealed that exosomes mediated intracellular communication 28,29 .…”

“…These molecules include lncRNAs, microRNAs (miRNAs), messenger RNAs (mRNAs), and proteins 27 . Macrophages secret and transmit certain functional proteins and RNAs to affect various kinds of cells, such as fibroblast and epithelial cells 28,29 . Previous research demonstrates that osteoarthritic chondrocytes secret exosome-like vesicles to facilitate the production of IL-1β in macrophages and aggravate OA progression 30 .…”