Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.
Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis.
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DOI：
10.1038/ncomms8158
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发表时间：
2015-05-18
影响因子：
16.6
通讯作者：
Habtezion A
中科院分区：
文献类型：
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作者：
Xue J;Sharma V;Hsieh MH;Chawla A;Murali R;Pandol SJ;Habtezion A
慢性胰腺炎(CP)是一种进行性、不可逆转的炎症性和纤维性疾病，无法治愈。与急性胰腺炎不同，我们发现激活的巨噬细胞(AAM)在小鼠和人类CP中占主导地位。AAM依赖于IL-4和IL-13信号，我们发现缺乏IL-4Rα、髓系特异性IL-4Rα和IL-4/IL-13的小鼠较不容易发生胰腺纤维化。此外，我们还证明了小鼠和人胰腺星状细胞(PSCs)是IL-4/IL-13的来源。值得注意的是，我们发现，在人类体外研究中以及在已建立的小鼠CP中，对IL-4/IL-13的药物抑制可以减少胰腺AAM和纤维化。我们确定了巨噬细胞在胰腺纤维化中的关键作用，并反过来将PSCs作为巨噬细胞替代激活的重要诱导物。我们的研究挑战并确定了巨噬细胞和PSCs之间的串扰所涉及的通路，这些通路可以靶向逆转或阻止胰腺纤维化的进展。
Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis, we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on IL-4 and IL-13 signaling and we show that mice lacking IL-4Rα, myeloid specific IL-4Rα, and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex-vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage alternative activation. Our study challenges and identifies pathways involved in cross talk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.