摘要：SummaryDesmoplasia around pancreatic lesions is a barrier for immune cells and a hallmark of developing and established pancreatic cancer. However, the contribution of the innate immune system to this process is ill-defined. Using the KC mouse model and primary cellsin vitro, we show that alternatively activated macrophages (AAM) crosstalk with pancreatic lesion cells and pancreatic stellate cells (PSCs) to mediate fibrosis and progression of lesions. TGFβ1 secreted by AAM not only drives activation of quiescent PSCs but also in activated PSCs upregulates expression of TIMP1, a factor previously shown as crucial in fibrosis. Once activated, PSCs auto-stimulate proliferation via CXCL12. Furthermore, we found that TIMP1/CD63 signaling mediates PanIN lesion growth and TGFβ1 contributes to a cadherin switch and drives structural collapse of lesions, indicating a potential progression step. Taken together, our data indicate TGFβ1 produced by Ym1+ AAM as a major driver of processes that initiate the development of pancreatic cancer.Graphical abstractDisplay OmittedFor a Figure360 author presentation of this figure, seehttps://doi.org/10.1016/j.isci.2022.104327Highlights•Ym1+macrophages are the main drivers of fibrosis in developing mouse PDA•Ym1+macrophages are the primary producers of TGFβ1 and TIMP1•TGFβ1 activates quiescent PSCs and induces them to produce αSMA•TGFβ1 can cause a collapsed PanIN structure via an EMT-like eventMicroenvironment; Immunology; Cancer
