Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.
Int Immunopharmacol. 2022 Jul;108:108777. doi: 10.1016/j.intimp.2022.108777. Epub 2022 Apr 20.
Severe acute pancreatitis (SAP), as a typical acute inflammatory injury disease, is one of the acute gastrointestinal diseases with a remarkable mortality rate. Macrophages, typical inflammatory cells involved in SAP, play an important role in the pathogenesis of SAP, which are separated into proinflammation M1 and antiinflammation M2. Growth and differentiation factor 11 (GDF11), as a member of the TGF-β family also called BMP-11, has been discovered to suppress inflammation. However, the mechanism by which GDF11 inhibits inflammation and whether it can ameliorate SAP are still elusive. The present research aimed to investigate the roles of GDF11 in SAP and the potential immunomodulatory effect of macrophage polarization. The mouse and rat SAP model were constructed by caerulein and retrograde injection of sodium taurocholate respectively. The effects of GDF11 on SAP were observed by serology, histopathology and tissue inflammation, and the effects of GDF11 on the polarization of macrophages in vivo were observed. Raw264.7 and THP1 crells were used to study the effect of GDF11 on macrophage polarization in vitro. To further investigate the causal link underneath, our team first completed RNA and proteome sequencing, and utilized specific suppressor to determine the implicated signal paths. Herein, we discovered that GDF11 alleviated the damage of pancreatic tissues in cerulein induced SAP mice and SAP rats induced by retrograde injection of sodium taurocholate, and further found that GDF11 facilitated M2 macrophage polarization and diminished M1 macrophage polarization in vivo and in vitro. Subsequently, we further found that the regulation of GDF11 on macrophage polarization through TGFβR1/smad2 pathway. Our results revealed that GDF11 ameliorated SAP and diminished M1 macrophage polarization and facilitated M2 macrophage polarization. The Role of GDF11 in modulating macrophage polarization might be one of the mechanisms by which GDF11 played a protective role in pancreatic tissues during SAP.
重症急性胰腺炎（SAP）作为一种典型的急性炎症损伤性疾病，是一种具有显著死亡率的急性胃肠道疾病。巨噬细胞是 SAP 中涉及的典型炎症细胞，在 SAP 的发病机制中发挥重要作用，可分为促炎 M1 和抗炎 M2。生长分化因子 11（GDF11）作为 TGF-β家族的成员，也称为 BMP-11，已被发现可抑制炎症。然而，GDF11 抑制炎症的机制以及它是否可以改善 SAP 仍不清楚。本研究旨在探讨 GDF11 在 SAP 中的作用以及巨噬细胞极化的潜在免疫调节作用。通过胆酸钠逆行注射和蛙皮素分别构建了小鼠和大鼠 SAP 模型。通过血清学、组织病理学和组织炎症观察 GDF11 对 SAP 的影响，并观察 GDF11 对体内巨噬细胞极化的影响。使用 Raw264.7 和 THP1 细胞在体外研究 GDF11 对巨噬细胞极化的影响。为了进一步探讨潜在的因果关系，我们首先完成了 RNA 和蛋白质组测序，并利用特异性抑制剂来确定涉及的信号通路。研究结果发现，GDF11 减轻了胆酸钠逆行注射诱导的 SAP 大鼠和蛙皮素诱导的 SAP 小鼠胰腺组织损伤，进一步发现 GDF11 促进了体内和体外 M2 巨噬细胞极化，并减少了 M1 巨噬细胞极化。随后，我们进一步发现 GDF11 通过 TGFβR1/smad2 通路调节巨噬细胞极化。我们的研究结果表明，GDF11 改善了 SAP，减少了 M1 巨噬细胞极化，并促进了 M2 巨噬细胞极化。GDF11 调节巨噬细胞极化的作用可能是 GDF11 在 SAP 期间发挥胰腺组织保护作用的机制之一。
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