巨噬細胞在腹膜纖維化中扮演的角色

Abstract

腎病末期的病患，經由透析以及移植的方式來維持腎功能的運作，而腹膜透析相較於血液透析擁有多項優點，包括可在家自行操作、價格低廉等因素，使病患們在生活品質有所提升，但腹膜透析的病患在長期的治療下，常常會導致第一型的腹膜纖維化，影響透析的效率，甚至是引發包囊性腹膜硬化症，造成生命的危險。在我們先前的研究中，發現間皮下纖維母細胞才是造成纖維化的主要來源，且也得知巨噬細胞在這當中有很大的影響，因此巨噬細胞在腹膜纖維化所扮演的角色，正是這篇要探討的地方。 在正常小鼠的腹腔中，巨噬細胞最主要的族群是由卵黃分化成的CD11bhi F4/80hi ，約佔90%，表現較高的M2 基因Arg1；另一群是來自於骨髓的CD11bint F4/80int表現較高的 M1 基因 Il-1 β、Il-12以及Tnf-α，在腹膜受到傷害後，CD11bhi F4/80hi 的族群會消失，取而代之的是CD11bint F4/80int 這群發炎性巨噬細胞。隨著時間的推進，發炎性巨噬細胞會由 Ly6C+ 轉變為 Ly6C - 並且由MHCII - 轉變成MHCII + ，在基因表現上從促發炎相關的基因 Il-1 β、Mip-1 α、Mip-2 轉變為促纖維化相關的 Ccl17、Ccl22、Arg1。在病理學上，次氯酸納的刺激會造成腹膜中巨噬細胞的堆積及肌纖維母細胞的增生。使用Csf1r cre；iDTR 的小鼠，藉由白喉毒素專一的去除所有表現Colony stimulating factor 1 receptor (CSF1R) 的細胞，來達到去除巨噬細胞的效果，雖然在去除巨噬細胞以及抑制纖維化上有非常顯著的效果，但在陳怡婷醫師的研究中發現肝細胞及腎臟中的細胞都會表現 CSF1R，故此品系的老鼠不適合用來研究巨噬細胞。在次氯酸鈉刺激下，腹腔中的CD11bhi F4/80hi 會消失，又稱為 Macrophage disappearance reaction （ MDR ），這些消失的細胞一部分會凋亡，一部分會遷移到網膜中或是黏在腹膜上，而黏在腹膜上巨噬細胞或許會與間皮細胞交互作用影響細胞激素的分泌，或許會參與白血球的浸潤以及纖維化的產生，這些都有待之後進一步的探討。 總結來說，腹膜受到傷害後，腹腔中最主要的族群CD11bhi F4/80hi 會黏在腹膜上及遷移到網膜中，同時會有大量的CD11bint F4/80int 發炎性巨噬細胞從血液中浸潤到腹腔，並分化成 M1 型，隨著時間推進，再慢慢轉變成促纖維化的 M2 型，然而從循環來或是組織中的巨噬細胞在纖維化中扮演的角色有哪些異同，還有待進一步的研究。

Peritoneal dialysis (PD) is one of the therapies for end-stage renal disease (ESRD). There are more advantages for PD than Hemodialysis (HD) including the convenience of home therapy and cost-effective. However, long-term PD leads to peritoneal damage and subsequently to peritoneal fibrosis. Unfortunately, some of them would become encapsulating peritoneal sclerosis (EPS). In our previous research, we found that submesothelial fibroblasts are the major source of myofibroblasts. And we also know macrophages are very important in peritoneal fibrosis. We try to figure out how macrophage play the role during peritoneal fibrosis. In the peritoneal cavity, the dominant population is CD11bhi F4/80hi. They are differentiated from yolk sac progenitor cell and express higher M2 gene like Arg1. The other population is CD11bint F4/80int which are express higher M1 genes likes Il-1 β、Il-12,and Tnf-α. After a peritoneal injury, CD11bhi F4/80hi undergo macrophage disappearance reaction (MDR) and CD11bint F4/80int will be the dominant population. During the fibrosis, Ly6C expression decrease and MHCII increase in inflammatory macrophages. In the early stage, inflammatory macrophage would express pro-inflammatory genes including Il-1 β, Mip-1 α,and Mip-2. Then they will switch to the pro-fibrotic cell type which expresses Ccl17, Ccl22, and Arg1. After hypochlorite injury, we observed that many macrophages accumulating in the peritoneum. Selective macrophages ablation in Csf1r-Cretg ; iDTR mice attenuated peritoneal fibrosis and decreased a-SMA+ myofibroblast accumulation after diphtheria toxin injection. However, Csf1r also express in hepatocytes and kidney cells in this mice. It is not a good model for macrophage researchThis strain is not suitable for further macrophage research. After When an peritoneal injury, CD11bhi F4/80hi will disappear, One of them undergo apoptosis, others will attach on peritoneum or migrate to omentum. It is unclear that how they crosstalk to mesothelial cell or recruit leukocytes. In conclusion, the dominate population CD11bhi F4/80hi disappear in peritoneal cavity and attach on mesothelial cell or migrate to omentum after hypochlorite injury. At the same time, massive macrophage recruit from circulation which express CD11bint F4/80int and differentiate intoto M1 type. During the fibrosis, the phenotype of inflammatory macrophages would become M2 type. However, the different between tissue resident or circulating macrophages during the peritoneal fibrosis needs further study.