小鼠巨噬细胞ANA-1的诱导分化及其不同分型在叶酸性肾病中的作用
摘要
研究背景：近年来不同活化状态的巨噬细胞在肾间质纤维化发展过程中的不同作用受到愈来愈多的重视。各种因素引起肾脏损伤时，循环中的巨噬细胞浸润到肾脏，根据组织微环境的不同，活化为M1型的巨噬细胞促进肾脏炎症发展，M2型巨噬细胞释放IL-4、IL-13、IL-10等调节因子促进组织炎症向组织恢复方向发展。目前诱导巨噬细胞表型分化的分子较多，但共刺激分子特别是在免疫炎症反应中起重要作用的B7-H3分子以及不同表型巨噬细胞在肾小管间质纤维化中的作用研究较少。
目的：本实验使用不同方法刺激小鼠巨噬细胞ANA-1诱导出不同表型巨噬细胞，比较不同条件刺激下各表型巨噬细胞表达蛋白及分泌因子的差异，建立起ANA-1的表型分化体系，同时研究B7-H3对ANA-1表型的影响，为B7-H3的临床应用提供理论依据。此外，应用脂多糖（LPS）或IL-4分别刺激的ANA-1输入到小鼠体内，观察不同条件刺激下的巨噬细胞对小鼠肾小管间质纤维化的影响。
方法:1.在1640和FBS培养ANA-1巨噬细胞的过程中，分别加用LPS、IL-4、B7-H3单克隆抗体（简称B7-H3mAb）、B7-H3mAb+LPS、B7-H3mAb+IL-4，同时设立空白对照组、小鼠IgG对照组，培养24小时后收取细胞及上清液，流式细胞术检测诱导型一氧化氮合成酶(iNOS)、巨噬细胞甘露糖受体（CD206）的蛋白表达水平，酶联免疫吸附试验（ELISA）检测细胞上清液IL-10、TNF-α的表达。2.采用两次腹腔注射叶酸的方法建立肾小管间质纤维化模型，CD1小鼠随机分为正常对照组、叶酸组、LPS+叶酸组、IL-4+叶酸组，分别于第14天和21天处死小鼠，留取血标本测肌酐（Cr）、尿素(UN)、尿酸(UA)水平，摘取右肾行常规HE染色、MASSON染色及F4/80巨噬细胞、ɑ平滑肌肌动蛋白（ɑ-SMA）、胶原蛋白I（COLI）免疫组织化学染色。
结果：第一部分：1.ANA-1经LPS刺激24h后B7-H3的表达升高，而IL-4刺激24h后的B7-H3的表达降低，差异均有统计学意义（P<0.05）；2.与空白对照组相比，LPS组高表达iNOS，加入B7-H3mAb后iNOS的表达明显降低，差异有统计学意义（P<0.05）；3.CD206在各组均高表达；4.与空白对照组相比，IL-4组及IL-4+B7-H3mAb组产生的IL-10明显增加（P<0.05），LPS组、B7-H3mAb组和LPS+B7-H3mAb组则无明显差别；TNF-α的水平与空白对照组相比IL-4+B7-H3mAb组虽有统计学意义，但变化不大，其他五组与空白对照组相比无明显差异。第二部分：1.HE染色和Masson染色显示正常对照组肾脏正常，叶酸组、LPS+叶酸组、IL-4+叶酸组小鼠UN、Cr、UA明显升高，肾小管间质纤维化，肾损伤严重程度LPS+叶酸组最重，叶酸组次之，IL-4+叶酸组最轻。2.免疫组织化学结果：两周时叶酸组、LPS+叶酸组、IL-4+叶酸组可见F4/80+巨噬细胞浸润，ɑ-SMA和COLI的表达量均明显高于正常对照组（P<0.05），模型组间无明显差别；三周时，ɑ-SMA的表达在IL-4+叶酸组明显低于LPS+叶酸组和叶酸组(P<0.05)，COLI的表达，LPS+叶酸组最高，叶酸组次之，IL-4+叶酸组最低，差异有统计学意义（P<0.05）。结论：第一部分：1.1μg/mlLPS刺激ANA-1上调iNOS的水平，向M1型巨噬细胞极化并上调B7-H3的表达，B7-H3mAb下调LPS活化的ANA-1iNOS的表达。
2.10ng/mlIL-4刺激ANA-1下调B7-H3的表达，并促进IL-10的分泌，向M2型巨噬细胞极化。第二部分：1.两次240mg/kg叶酸腹腔注射后，叶酸组小鼠肾脏肾小管间质明显纤维化，免疫组织化学示肾间质F4/80+巨噬细胞数量、COLⅠ及ɑ-SMA明显增加，该方法成功建立肾小管间质纤维化模型。2.LPS和IL-4分别诱导的巨噬细胞输入到叶酸性肾病小鼠体内，LPS刺激的巨噬细胞明显加重叶酸性肾病小鼠肾小管间质的损伤，具体表现为肾小管间质COLⅠ的产生和小管间质纤维化的面积明显增加；而IL-4活化的M2型巨噬细胞抑制叶酸性肾病小鼠肾小管间质纤维化，具体表现在肾小管间质COLⅠ及ɑ-SMA的产生以及小管间质纤维化的面积明显减少。
Background:The various roles of different state of macrophages in the process of renal interstitial fibrosis have been studied more in recent years. Macrophages infiltrate from circulation to the kidneys when kidney damage occurred due to various pathogens. Depending on the tissue microenvironment, classically activated macrophages(M1) promoted the development of kidney inflammation while the alternatively activated macrophages(M2) relieved tissue inflammation through releasing regulatory factors like IL-4,IL-13, IL-10. A lot of molecules induced the phenotype differentiation of macrophage, but less were reported about the roles of costimulatory molecules involved in the process, especially B7-H3which plays an important role in the inflammatory reaction. The actions of different phenotypes of macrophages in renal tubulointerstitial fibrosis were also less studied.
Objective:In this study, different methods were used to stimulate murine macrophage (ANA-1) and induced different phenotypes of macrophages. By comparing different cytokine production with various stimulation, phenotypic differentiation methods of ANA-1were established. This will provide theoretical basis for the clinical application of B7-H3. In addition, macrophages stimulated by lipopolysaccharide(LPS) or IL-4were injected into mouse with folic acid nephropathy and followed effects on tubulointerstitial fibrosis were explored.
Methods:1.When cultured by1640and fetal bovine serum(FBS), ANA-1with LPS, IL-4, B7-H3monoclonal antibody (B7-H3mAb), B7-H3mAb+LPS, B7-H3mAb+IL-4, blank and mice IgG control group were established. The cells and supernatant were collected after a24hours'culture. Inducible nitric oxide synthase (iNOS) and macrophage mannose receptor (CD206) were detected by flow cytometry. IL-10, tumor necrosis factor a(TNF-a) level were tested by enzyme-linked immunosorbent assay (ELISA).2.CD1mouse were randomly assigned to four groups:normal control group, folic acid group(FA group), LPS+FA group, IL-4+FA group. The model of interstitial fibrosis was induced with240mg/kg of folic acid (FA) by intraperitoneal injection. Five mouse in each group were sacrificed on the14th and21th day. Blood was collected to detect blood urea nitrogen(UN), creatinine(Cr), uric acid (UA) respectively. Samples of kidneys were processed for hematoxylineosin stain(HE), Masson trichrome stain and F4/80macrophages, α-smooth muscle actin (a-SMA), collagen I (COLI) detected by immunohistochemical stain(IHC).
Results:The first part:1. The expression of B7-H3on ANA-1stimulated with LPS was up-regulated while decreased with IL-4(P<0.05);2. Compared with the blank control group, LPS group had a high protein expression of iNOS, and decreased significantly when cocultured with B7-H3mAb (P<0.05);3. The high expression of CD206was seen in each group without obvious change;4. Compared with the blank control group, the production of IL-10in IL-4group and IL-4+B7-H3mAb group significantly increased (P<0.05), while no significant was found in LPS group, B7-H3mAb group and LPS+B7-H3mAb group; Compared with the blank control group, although the level of TNF-a in the IL-4+B7-H3mAb group had statistical difference, the change was not obvious and the other five groups had no significant difference. The second part:1. After two times of240mg/kg FA administration by intraperitoneal injection, serum UN, Cr, UA level significantly increased in FA group. HE staining and Masson staining showed LPS+FA group and IL-4+FA group had different renal tubulointerstitial fibrosis. The severity of fibrosis in LPS+FA folic acid group was the worst, followed by FA group and last by IL-4+FA group.2. Immunohistochemistry results:the FA group, LPS+FA group, IL-4+FA group showed a high level of F4/80+macrophage infiltration at two weeks, the expression of a-SMA and COLI were significantly higher than the normal control group, there was no significant difference among three model groups. At the third week, the expression of a-SMA in IL-4+FA group was lower than which in FA group and LPS+FA group (P<0.05), the expression of COL I in LPS+FA group was dominant, followed by FA group and IL-4+FA group weakest (P<0.05).
Conclusion:The first part:1.ANA-1stimulated by1μg/ml LPS up-regulated the level of iNOS, polarized to M1macrophages and up-regulated expression of B7-H3. B7-H3mAb down-regulated the increased iNOS induced by LPS.2. ANA-1with lOng/ml IL-4increased the secretion of IL-10, polarized macrophages to M2phenotypic with lower expression of B7-H3. The second part:1. After two times of240mg/kg FA administration by intraperitoneal injection, serum UN, Cr, UA level significantly increased. HE and Masson staining showed a large number of inflammatory cell infiltration in the tubulointerstitial fibrosis area. Immunohistochemistry showed a significant increase of the number of F4/80+macrophages and the expression of COL I and a-SMA. Tubulointerstitial fibrosis model was successfully established by FA.2. LPS stimulated macrophages exacerbated significantly the severity of tubulointerstitial fibrosis in folic acid nephropathy, manifested by the enlarged area of interstitial fibrosis and increased COLI expression; whereas macrophages activated by IL-4inhibited the development of tubulointerstitial fibrosis with the decreased COL I and a-SMA expression in the folic acid nephropathy.
目的：本实验使用不同方法刺激小鼠巨噬细胞ANA-1诱导出不同表型巨噬细胞，比较不同条件刺激下各表型巨噬细胞表达蛋白及分泌因子的差异，建立起ANA-1的表型分化体系，同时研究B7-H3对ANA-1表型的影响，为B7-H3的临床应用提供理论依据。此外，应用脂多糖（LPS）或IL-4分别刺激的ANA-1输入到小鼠体内，观察不同条件刺激下的巨噬细胞对小鼠肾小管间质纤维化的影响。
方法:1.在1640和FBS培养ANA-1巨噬细胞的过程中，分别加用LPS、IL-4、B7-H3单克隆抗体（简称B7-H3mAb）、B7-H3mAb+LPS、B7-H3mAb+IL-4，同时设立空白对照组、小鼠IgG对照组，培养24小时后收取细胞及上清液，流式细胞术检测诱导型一氧化氮合成酶(iNOS)、巨噬细胞甘露糖受体（CD206）的蛋白表达水平，酶联免疫吸附试验（ELISA）检测细胞上清液IL-10、TNF-α的表达。2.采用两次腹腔注射叶酸的方法建立肾小管间质纤维化模型，CD1小鼠随机分为正常对照组、叶酸组、LPS+叶酸组、IL-4+叶酸组，分别于第14天和21天处死小鼠，留取血标本测肌酐（Cr）、尿素(UN)、尿酸(UA)水平，摘取右肾行常规HE染色、MASSON染色及F4/80巨噬细胞、ɑ平滑肌肌动蛋白（ɑ-SMA）、胶原蛋白I（COLI）免疫组织化学染色。
结果：第一部分：1.ANA-1经LPS刺激24h后B7-H3的表达升高，而IL-4刺激24h后的B7-H3的表达降低，差异均有统计学意义（P<0.05）；2.与空白对照组相比，LPS组高表达iNOS，加入B7-H3mAb后iNOS的表达明显降低，差异有统计学意义（P<0.05）；3.CD206在各组均高表达；4.与空白对照组相比，IL-4组及IL-4+B7-H3mAb组产生的IL-10明显增加（P<0.05），LPS组、B7-H3mAb组和LPS+B7-H3mAb组则无明显差别；TNF-α的水平与空白对照组相比IL-4+B7-H3mAb组虽有统计学意义，但变化不大，其他五组与空白对照组相比无明显差异。第二部分：1.HE染色和Masson染色显示正常对照组肾脏正常，叶酸组、LPS+叶酸组、IL-4+叶酸组小鼠UN、Cr、UA明显升高，肾小管间质纤维化，肾损伤严重程度LPS+叶酸组最重，叶酸组次之，IL-4+叶酸组最轻。2.免疫组织化学结果：两周时叶酸组、LPS+叶酸组、IL-4+叶酸组可见F4/80+巨噬细胞浸润，ɑ-SMA和COLI的表达量均明显高于正常对照组（P<0.05），模型组间无明显差别；三周时，ɑ-SMA的表达在IL-4+叶酸组明显低于LPS+叶酸组和叶酸组(P<0.05)，COLI的表达，LPS+叶酸组最高，叶酸组次之，IL-4+叶酸组最低，差异有统计学意义（P<0.05）。结论：第一部分：1.1μg/mlLPS刺激ANA-1上调iNOS的水平，向M1型巨噬细胞极化并上调B7-H3的表达，B7-H3mAb下调LPS活化的ANA-1iNOS的表达。
2.10ng/mlIL-4刺激ANA-1下调B7-H3的表达，并促进IL-10的分泌，向M2型巨噬细胞极化。第二部分：1.两次240mg/kg叶酸腹腔注射后，叶酸组小鼠肾脏肾小管间质明显纤维化，免疫组织化学示肾间质F4/80+巨噬细胞数量、COLⅠ及ɑ-SMA明显增加，该方法成功建立肾小管间质纤维化模型。2.LPS和IL-4分别诱导的巨噬细胞输入到叶酸性肾病小鼠体内，LPS刺激的巨噬细胞明显加重叶酸性肾病小鼠肾小管间质的损伤，具体表现为肾小管间质COLⅠ的产生和小管间质纤维化的面积明显增加；而IL-4活化的M2型巨噬细胞抑制叶酸性肾病小鼠肾小管间质纤维化，具体表现在肾小管间质COLⅠ及ɑ-SMA的产生以及小管间质纤维化的面积明显减少。
Background:The various roles of different state of macrophages in the process of renal interstitial fibrosis have been studied more in recent years. Macrophages infiltrate from circulation to the kidneys when kidney damage occurred due to various pathogens. Depending on the tissue microenvironment, classically activated macrophages(M1) promoted the development of kidney inflammation while the alternatively activated macrophages(M2) relieved tissue inflammation through releasing regulatory factors like IL-4,IL-13, IL-10. A lot of molecules induced the phenotype differentiation of macrophage, but less were reported about the roles of costimulatory molecules involved in the process, especially B7-H3which plays an important role in the inflammatory reaction. The actions of different phenotypes of macrophages in renal tubulointerstitial fibrosis were also less studied.
Objective:In this study, different methods were used to stimulate murine macrophage (ANA-1) and induced different phenotypes of macrophages. By comparing different cytokine production with various stimulation, phenotypic differentiation methods of ANA-1were established. This will provide theoretical basis for the clinical application of B7-H3. In addition, macrophages stimulated by lipopolysaccharide(LPS) or IL-4were injected into mouse with folic acid nephropathy and followed effects on tubulointerstitial fibrosis were explored.
Methods:1.When cultured by1640and fetal bovine serum(FBS), ANA-1with LPS, IL-4, B7-H3monoclonal antibody (B7-H3mAb), B7-H3mAb+LPS, B7-H3mAb+IL-4, blank and mice IgG control group were established. The cells and supernatant were collected after a24hours'culture. Inducible nitric oxide synthase (iNOS) and macrophage mannose receptor (CD206) were detected by flow cytometry. IL-10, tumor necrosis factor a(TNF-a) level were tested by enzyme-linked immunosorbent assay (ELISA).2.CD1mouse were randomly assigned to four groups:normal control group, folic acid group(FA group), LPS+FA group, IL-4+FA group. The model of interstitial fibrosis was induced with240mg/kg of folic acid (FA) by intraperitoneal injection. Five mouse in each group were sacrificed on the14th and21th day. Blood was collected to detect blood urea nitrogen(UN), creatinine(Cr), uric acid (UA) respectively. Samples of kidneys were processed for hematoxylineosin stain(HE), Masson trichrome stain and F4/80macrophages, α-smooth muscle actin (a-SMA), collagen I (COLI) detected by immunohistochemical stain(IHC).
Results:The first part:1. The expression of B7-H3on ANA-1stimulated with LPS was up-regulated while decreased with IL-4(P<0.05);2. Compared with the blank control group, LPS group had a high protein expression of iNOS, and decreased significantly when cocultured with B7-H3mAb (P<0.05);3. The high expression of CD206was seen in each group without obvious change;4. Compared with the blank control group, the production of IL-10in IL-4group and IL-4+B7-H3mAb group significantly increased (P<0.05), while no significant was found in LPS group, B7-H3mAb group and LPS+B7-H3mAb group; Compared with the blank control group, although the level of TNF-a in the IL-4+B7-H3mAb group had statistical difference, the change was not obvious and the other five groups had no significant difference. The second part:1. After two times of240mg/kg FA administration by intraperitoneal injection, serum UN, Cr, UA level significantly increased in FA group. HE staining and Masson staining showed LPS+FA group and IL-4+FA group had different renal tubulointerstitial fibrosis. The severity of fibrosis in LPS+FA folic acid group was the worst, followed by FA group and last by IL-4+FA group.2. Immunohistochemistry results:the FA group, LPS+FA group, IL-4+FA group showed a high level of F4/80+macrophage infiltration at two weeks, the expression of a-SMA and COLI were significantly higher than the normal control group, there was no significant difference among three model groups. At the third week, the expression of a-SMA in IL-4+FA group was lower than which in FA group and LPS+FA group (P<0.05), the expression of COL I in LPS+FA group was dominant, followed by FA group and IL-4+FA group weakest (P<0.05).
Conclusion:The first part:1.ANA-1stimulated by1μg/ml LPS up-regulated the level of iNOS, polarized to M1macrophages and up-regulated expression of B7-H3. B7-H3mAb down-regulated the increased iNOS induced by LPS.2. ANA-1with lOng/ml IL-4increased the secretion of IL-10, polarized macrophages to M2phenotypic with lower expression of B7-H3. The second part:1. After two times of240mg/kg FA administration by intraperitoneal injection, serum UN, Cr, UA level significantly increased. HE and Masson staining showed a large number of inflammatory cell infiltration in the tubulointerstitial fibrosis area. Immunohistochemistry showed a significant increase of the number of F4/80+macrophages and the expression of COL I and a-SMA. Tubulointerstitial fibrosis model was successfully established by FA.2. LPS stimulated macrophages exacerbated significantly the severity of tubulointerstitial fibrosis in folic acid nephropathy, manifested by the enlarged area of interstitial fibrosis and increased COLI expression; whereas macrophages activated by IL-4inhibited the development of tubulointerstitial fibrosis with the decreased COL I and a-SMA expression in the folic acid nephropathy.
引文
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