Abstract
摘要:免疫記憶長久以來被認為是後天免疫細胞專有之功能,然而近期發現先天性免疫細 胞(例如:單核球細胞和巨噬細胞)在遭遇感染、疫苗接種或是環境因子刺激下,會透 過重塑代謝功能和表觀遺傳調節產生免疫記憶反應。這一類源於骨髓的先天性免疫 細胞所產生的免疫記憶功能,被稱為訓練性先天免疫。研究顯示,不良飲食攝取可 被視為一種形式的環境因子刺激,其在先天免疫細胞群引起的訓練性免疫反應對疾 病可能有害,並影響被訓練的先天免疫細胞在病理環境下的功能。雖然產生訓練性 先天免疫的詳細機制尚待深入探討,由飲食因子所引起的訓練性先天免疫與人類日 常生活緊密相關,而其對疾病之影響仍待探究。 各項飲食因子中,高度鹽份(鈉)攝取為主要造成人類疾病和死亡的成因。過去針對 鹽分攝取和健康危害的研究,多著墨於高鹽飲食對血管病變或是高血壓之影響。但 近年研究證實,高鹽飲食可直接影響免疫細胞功能,並加劇對自體免疫疾病造成之 傷害。值得注意的是,雖然高鹽飲食會增加高血壓和腦出血的機率,但是否高鹽飲 食會加劇腦出血發生後的病理傷害,或是高鹽飲食是否會誘發巨噬細胞產生對中樞 神經系統有害的訓練性先天免疫反應,仍屬未知。 腦出血屬於中風的一種形式,源於顱內血管破裂使血液進入腦實質產生血塊,血塊 壓迫和滲入之血液代謝物促使神經細胞死亡。目前腦出血有效治療方式仍僅限外科 手術,其病理分子機轉及藥物治療策略十分有限。腦出血所誘發腦部常駐性巨噬細 胞和血源性巨噬細胞活化,透過細胞亞型反應調節,可能加重腦部傷害,或可促進 血塊吸收和神經修復,此病理特徵提供了腦出血疾病模式,作為探討高鹽飲食是否 會透過誘發巨噬細胞,產生有害之訓練性先天免疫反應,進而加劇腦部病理損傷之 研究策略。 本計畫欲藉由腦出血疾病模型,探討高鹽攝取是否會在心血管病癥未形成前,透過 對免疫系統的影響,加劇腦部產生損傷時之病理傷害。而可能的機轉為,高鹽攝取 將改變巨噬細胞和骨髓中前驅細胞之代謝功能和表觀遺傳調節反應,促使巨噬細胞 產生不利腦部修復之訓練性先天免疫反應。
Abstract: Immune memory has long been considered an exclusive feature for the adaptive immunity. However, recent advances reveal that innate immune cells such as monocytes and macrophages can also display adaptive characteristics after infection, vaccination, and environmental challenges through metabolic and/or epigenetic reprogramming. While these observations led to the discovery of trained innate immunity, the mechanism through which trained memory is induced in the specific myeloid population remains elusive. Recent demonstration of trained immunity induced by dietary factors provides a strong argument that diets among many other environmental challenges can precipitate maladaptive trained innate immune responses. This type of maladaptation could subsequently lead to diseases and deleterious pathological consequence. Therefore, efforts towards a better understanding of how dietary factors “train” innate immune cells are in dire need. In particular, high salt diet (HSD) is gaining attention because it accounts for half of the diet-related deaths and is a leading dietary risk factor for mortality worldwide. While studies suggest excessive sodium consumption is associated with the development of angiopathy and hypertension, high sodium intake can directly impact immune system function prior to vascular malfunction. Importantly, whether HSD can provoke trained immunity in monocytes and macrophages leading to potentially detrimental immune responses once brain injury happens is largely unknown. ICH is a devastating form of stroke that is initiated by rupture of a parenchymal blood vessel which results in blood leakage into the brain and subsequent formation of hematoma and brain injury. This elicits a series of responses from the professional phagocyte CNS-resident macrophages (microglia) and peripheral monocyte-derived macrophages (MDMs) whose extensive phenotypic heterogeneity contribute to both brain damage and repair. These pathological characters make ICH an ideal model to study the effect of HSD-induced trained innate immunity in brain injury. In this project, we propose to (1) investigate whether prolonged high sodium intake exacerbates ICH outcome in vivo even in the absence of hypertension; and (2) to explore whether HSD modulates phenotypic change in microglia and MDMs following injury, and (3) to test whether high sodium triggers immune memory in macrophages; and last, (4) whether macrophages are “trained” through metabolic and epigenetic reprogramming of the myeloid lineage progenitor cells from which new circulating macrophages derive. The findings from this proposal will provide a better understanding of how environmental factors, i.e. high salt diet, mechanistically influence immune processes. The results of this work will shed lights on HSD-mediated functional change in immune cells and may pave the road for new therapeutic interventions targeting salt-related diseases including ICH. Last, by studying whether and how HSD can provoke trained immunity, we hope to raise public awareness and advocate for a reduced-sodium diet and better immune health.
Keyword(s)
顱內出血
訓練性先天免疫反應
腦部常駐性巨噬細胞(微小膠細胞)
巨噬細胞
神經免疫學
心血管疾病
Intracerebral hemorrhage
Trained innate immunity
Microglia
Macrophages
Neuroimmunology
Cardiovascular disease