Hepatic Stellate Cell-derived IL-11 Exacerbates Liver Fibrosis via Interplay between HSCs and Macrophages

in C57/B6 mice, accompanied by a marked increase of M2 macrophages. Mechanistically, the autocrine signaling of IL-11 activated HSCs directly, potently enhancing the contractility, migration, and collagen production of HSCs through GP130-SFK-YAP pathway. Furthermore, IL-11 also functioned as a paracrine signal of HSCs activation that synergized with IL-4 to polarize macrophages into a profibrotic M2-like phenotype. This reprogramming was achieved through the coordinated activation of PI3K-mTOR signaling to promote TGF-β synthesis and STAT3 pathway to elevate chemokine levels. The necessity of macrophages in this process was proven when their depletion blunted the pro-fibrogenic effects of IL-11 overexpression. Consequently, therapeutic inhibition of IL-11 with a nanobody alleviated fibrosis and reversed macrophage polarization. Our findings proposed a self-amplifying loop where HSC-derived IL-11 directly activates fibrogenesis and simultaneously reprograms macrophages to create a feed-forward cycle that relentlessly drives disease progression.