Department of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo, Japan.
Gastroenterology. 2012 Apr;142(4):1010-1020.e9. doi: 10.1053/j.gastro.2011.12.054. Epub 2012 Jan 13.
BACKGROUND & AIMS: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein- and L-arginine-induced acute pancreatitis in mice.
Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages.
Almost all types of immune cells, except for CD11b(high)CD11c(-) cells, were detected in the pancreas of healthy mice. However, activated CD11b(high)CD11c(-) cells, including Gr-1(low) macrophages and Gr-1(high) cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2(-/-) mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b(high)CD11c(-)Gr-1(low) macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b(high)CD11c(-)Gr-1(low) macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1(low) macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b(high)CD11c(-)Gr-1(low) macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2.
Cerulein induction of pancreatitis in mice involves migration of CD11b(high)CD11c(-)Gr-1(low) macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.
急性胰腺炎是一种常见的炎症性疾病，由胰腺腺泡细胞损伤和随后的胰腺炎症引起，伴有白细胞募集。我们研究了固有免疫细胞（尤其是巨噬细胞）在鼠的亮氨酸脑啡肽和 L-精氨酸诱导的急性胰腺炎中的病理作用。
通过连续腹膜内给予亮氨酸脑啡肽诱导急性胰腺炎。我们测定血清淀粉酶和脂肪酶浓度、胰腺病理和浸润单核细胞的特征。我们进行联体共生手术以评估胰腺巨噬细胞的血液动力学。
在健康小鼠的胰腺中检测到几乎所有类型的免疫细胞，但除外 CD11b(high)CD11c(-)细胞。然而，在亮氨酸脑啡肽给药后，在受损的胰腺中检测到活化的 CD11b(high)CD11c(-)细胞，包括 Gr-1(low)巨噬细胞和 Gr-1(high)细胞（粒细胞和髓源性抑制细胞）。给予亮氨酸脑啡肽注射的 CCL2(-/-)小鼠发生的胰腺炎明显较轻，CD11b(high)CD11c(-)Gr-1(low)巨噬细胞浸润较少，但与亮氨酸脑啡肽注射的野生型小鼠相比，髓源性抑制细胞浸润相当。这些小鼠的联体共生和骨髓分析表明，CD11b(high)CD11c(-)Gr-1(low)巨噬细胞已从骨髓中移出。此外，给予亮氨酸脑啡肽注射的巨噬细胞特异性缺失信号转导和转录激活因子 3 的小鼠发生的胰腺炎较轻，Gr-1(low)巨噬细胞产生的肿瘤坏死因子-α少于给予亮氨酸脑啡肽的野生型小鼠，尽管两种菌株的 CD11b(high)CD11c(-)Gr-1(low)巨噬细胞的绝对数量相当。L-精氨酸诱导的急性胰腺炎需要 CCL2 通过受体 CCR2 诱导巨噬细胞迁移。
鼠亮氨酸脑啡肽诱导的胰腺炎涉及 CD11b(high)CD11c(-)Gr-1(low)巨噬细胞从骨髓中的迁移（由 CCL2 通过 CCR2 介导）和依赖信号转导和转录激活因子 3 的巨噬细胞激活。这些发现可能为急性胰腺炎提供新的治疗策略。
