Primed mesenchymal stem cells attenuate schistosomiasis fibrosis by enhancing macrophage subset switching and efferocytosis via Itgb2-Rac1 axis

Abstract The pathological hallmark of schistosomiasis is egg-induced granulomatous inflammation and the subsequent fibrosis in the liver; and mesenchymal stem cells have been explored for the treatment of schistosomiasis fibrosis. However, the underlying mechanisms are largely unknown. We demonstrated here that IFN-γ/ LPS-primed MSCs alleviate schistosomiasis fibrosis through promoting conversion of Ly6C hi CX3CR1 lo to pro-resolving Ly6C lo CX3CR1 hi . Importantly, primed MSCs promoted macrophage efferocytosis in the infected mice, and in vitro experiments confirmed the direct role of primed MSC on enhancement of macrophage efferocytosis, as well as its conversion to pro-resolving type. Mechanistically, primed MSC promoted β2 integrins(Itgb2) expression within macrophages; and Itgb2 blockade not only inhibited GTPase Rac1 activity, a key regulator of actin filament organization during efferocytosis, but also abolished the enhancement of primed MSCs on macrophage efferocytosis, suggesting that primed MSCs enhance efferocytosis via Itgb2-Rac1 axis. Moreover, either Itgb2 blockade or Rac1 inhibition within macrophages reversed the regulation of primed MSCs on macrophage subset switching, suggesting that primed MSCs promote macrophage subset conversion dependent on efferocytosis pathway. Taken together, this study demonstrates that primed MSCs attenuate schistosomiasis liver fibrosis by enhancing macrophage subset switch and efferocytosis via Itgb2-Rac1 axis, which offers novel insights into the therapeutic targets of MSC-based anti-fibrotic therapy.