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 αâsmooth muscle actin (αâSMA) 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 TGFâÎČ1 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 TGFâÎČ1âstimulated coculture system, a long noncoding RNA (lncRNA) named lncRNAâASLNCS5088 was enriched in M2 macrophageâderived exosomes. This lncRNA could be transferred with high efficiency to fibroblasts and acted as an endogenous sponge to adsorb microRNAâ200câ3p, resulting in increased GLS and αâSMA 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 αâSMA+ fibroblasts and alleviated the fibrosis of tissue after wound healing in vivo.âChen, J., Zhou, R., Liang, Y., Fu, X., Wang, D., Wang, C. Blockade of lncRNAâASLNCS5088âenriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 33, 12200â12212 (2019). http://www.fasebj.org