2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645381摘要：Th17細胞是能高度促進發炎反應的細胞，對於清除入侵的病原體占有極重要的角色，最近也發現 Th17細胞的異常活化與許多自體免疫疾病相關，也會惡化許多免疫相關疾病。白細胞介素-23 (IL-23) 會經由增加Th17細胞的IL-23受體以穩定並強化Th17細胞的活化，對於Th17細胞執行病原清除的功能 相當的重要。高鹽〔氯化鈉)飲食是當代非常普遍的疾病因子，過去的研究已發現高鹽飲食會影響Th17 細胞活化並惡化許多實驗性的免疫相關疾病，並與臨床上病患的自體免疫疾病盛行息息相關。雖然已 有研究顯示過度的鈉鹽攝取會增加皮膚的非滲透壓活性的鈉離子累積，因而活化IL-23/IL-17的相關細 胞活化以惡化免疫疾病，但那些用來證實相關理論的細胞培養實驗卻採用增加滲透壓活性的鈉鹽加入 一般的培養液中以達到活化巨嗜細胞與T細胞卻無法充分支持皮膚是高鹽飲食活化Th17細胞的器官。 事實上，當動物離開水上到陸地生活時，腎臟髓質會發展成具有相當高鈉離子濃度與尿素的組織以利 於尿液濃縮，再吸收水分回到體内。因此，如果高鈉離子會活化異常的免疫反應，那腎臟髓質必然需 要演化出拮抗或消弭該免疫異常反應的機制。目前有證據顯示半乳糖凝集素-3 (galectin-3)會透過抑制 樹突細胞在遭遇微生物時的IL-23製造以達到抑制Th17細胞的活化，並讓淋巴球往Th1分化。有趣的是 galectin-3在腎臟的腎小管上皮細胞，尤其是集尿管上皮細胞，與巨嗜細胞均大量表現。因此我們猜測 腎臟的galectin-3表現，可能是在演化過程中表現出來調節Th17細胞的過度活化，尤其是在面對腎髓 質間質内高鈉離子濃度或鹽分攝取進一步增加腎髓質間質内鈉離子濃度時。我們的初步實驗結果顯示 小鼠在高鹽攝取時腎臟的Th17細胞可能會被活化。因此我們提出此一三年計畫，首先要證實高鹽飲食 的確會造成腎臟的Th17細胞活化。我們的研究將利用細胞培養與小鼠餵食高鹽飲食來研究galectin-3 的表現與否是否影響巨嗜細胞及Th17細胞的活化。然後我們將利用基因改造小鼠將腎小管上皮細胞與 巨嗜細胞的galectin-3專一性地剔除，然後觀察對於腎臟處理鈉鹽的能力與Th17細胞的活化是否有影 響。經由本研究我們不僅可以釐清腎臟高量表現galectin-3的目的也可以進一步強調高鹽飲食對於腎臟 以及可能全身免疫系統的影響。我們希望能透過這個研究計畫探討腎臟内鈉離子，galectin-3與Th17 細胞之間的交互作用，並期望釐清腎臟在調節鈉離子與尿液濃縮時，如何避免異常的免疫反應。<br> Abstract: Th17 cells are highly pro-inflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases. IL-23 has a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23R and endowing Th17 cells with pathogenic effector functions. Increased salt (NaCl) intake, one of the prevalent environmental factors, has been shown to influence Th17 cells thereby aggravating murine experimental autoimmune encephalomyelitis. Although studies suggest that excessive salt intake exaggerates osmotically inactive sodium reservoir in skin, thereby activating IL-23/IL-17 axis and aggravating autoimmune disease, the need of additional osmotically active sodium in culture medium to activate macrophages/T cells in vitro does not support skin as the primary niche for salt-induced Th17 polarization. In fact very high concentration of sodium is found in renal medulla which is developed for urine concentration when animals leave water and try to survive on land. It is reasonable to speculate a counteracting mechanism for preventing Th17 cell activation by extraordinary sodium in renal medulla. To regulate Th17 response galectin-3 has been recently shown to play an inhibitory role through inhibition of IL-23 cytokine production by dendritic cells. Galectin-3 is highly expressed in tubular epithelial cells and macrophages of kidney. We are intrigued by the role of galectin-3 in regulating macrophages/Th17 cells in the hypertonic renal medulla whose osmotically active sodium is high and increases markedly after high salt diet (HSD). Our preliminary studies suggest the hypertonic renal medulla as the possible site for macrophages/Th17 cells activation by HSD. In this 3-year study, we will first confirm the activation of Th17 cells in kidneys of mice fed with HSD. We will then study the role of galectin-3 in activation of Th17 cells in kidneys of mice during HSD and in cell cultures. We will then dissect the specific role of cell-specific galectin-3 expressed in renal tubular epithelial cells and macrophages in the handling of sodium and activation of Th17 cells in kidneys during HSD using mice with cell-specific galectin-3 knockout. Through this study we will not only clarify the secret of high galectin-3 expression in kidney but also re-emphasize the biologic negative aspect of high salt intake on health of human body. We look forward to finding out novel targets to maintain the homeostasis of both sodium balance and immune status through understanding the cross-talk among sodium, galectin-3 and Th17 cells in kidneys.半乳糖凝集素-3高鹽飲食腎臟鈉鹽Th17細胞galectin-3high salt intakekidneysodiumTh17 cells