[Int J Mol Sci] 中性粒細胞重新進入肺的適應:動態平衡和疾病的新概念和意義

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Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasisand Disease

Vincent D. Giacalone , Camilla Margaroli , Marcus A. Mall and Rabindra Tirouvanziam

Int J Mol Sci.2020 Jan 28;21(3). Neutrophils have a prominent role in all human immune responses against any type of pathogenor stimulus. The lung sarea major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are wellknown for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to the irpotent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis(CF) and chronic obstructive pulmonary disease(COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury(TRALI). 中性粒細胞在人體對各種病原體或刺激的免疫反應中起著重要作用。肺部是主要的中性粒細胞儲存庫，中性粒細胞炎症是對感染性和非感染性刺激的主要反應。雖然中性粒細胞因其在清除細菌方面的重要作用而廣為人知，但它們也具有特定的機制來對抗病毒和真菌。當這些防禦機制在沒有感染的情況下異常激活時，通常會導致肺部炎症反應能力逐漸惡化。通過吞噬清除細菌是中性粒細胞的標誌性作用，而且這種作用機制已被廣泛研究。對中性粒細胞生物學的新研究表明，這個白細胞亞群具有高度的適應性，並發揮著不同的作用。特別令人感興趣的是，這些適應是如何通過它們清除感染和引起宿主組織損害的強大能力來影響肺部免疫反應的。中性粒細胞的適應特性和影響免疫反應的潛在性質意味著它們可能是未來免疫調節治療急需的目標。本文綜述了近年來中性粒細胞炎症機制的研究進展，重點介紹了造成巨大且日益嚴重公共衛生負擔的囊性纖維化(CF)、慢性阻塞性肺疾病(COPD)等慢性肺部疾病和輸血相關急性肺損傷(TRALI)等急性肺部炎性疾病對肺部的影響。Neutrophils comprise the largest proportion of circulating leukocytes in the human body and maintain a major presence in organs such as the lung. Consequently, despite being considered as terminally differentiated and endowed with a short lifespan after leaving the bonemarrow, they are a major player ininnate immunity. Their hallmark function is clearance of debris and pathogens through phagocytosis but they exhibit adiverse array of other immune functions. In addition to the direct phagocytosis of bacteria and fungi, they limit the spread of microbes by releasing neutrophil extracellular traps (NETs) made of DNA through a process known as NETosis. Although neutrophils are professional killers, they also have significant capacity to modulate the function of other immunecells. Diverse effector functions of secreted proteins, some of which are summarized in Table 1, are key for neutrophil adaptability and their far-reaching effects on immuneresponses.There is a rapidly increasing prevalence of chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) in the global population, in part due to increased exposure to air pollution. In addition, aging populations are faced with increased risk for common nosocomial infections such as bacterial pneumonia, which results in sustained neutrophil recruitment to the lung but reduce defficacy in clearing infections.Neutrophilic inflammation is also a key component of progressive lung damage in patients with CF, which is one of the most common fatal hereditary diseases. A greater understanding of pathological features of neutrophils in such lung pathologies is critical to improving treatment options for both acute and chronic inflammatory diseases.中性粒細胞在人體循環白細胞中所佔比例最大，主要存在於肺臟等器官中。因此，儘管它們被認為是在終末期分化的，且離開骨髓後壽命很短，但它們仍然是先天免疫的主要參與者。它們的標誌性功能是通過吞噬來清除碎片和病原體的，但它們表現出多種免疫功能。除了對細菌和真菌的直接吞噬作用外，它們還通過釋放由DNA組成的中性粒細胞胞外陷阱(NETs)，從而限制微生物的傳播。中性粒細胞雖然是職業殺手，但它們也有很強的調節其他免疫細胞功能的能力。分泌蛋白的不同效應功能(表1總結了一部分)是中性粒細胞適應性及其對免疫反應的深遠影響的關鍵。
在全球人口中，哮喘和慢性阻塞性肺疾病(COPD)等慢性炎症性肺部疾病的患病率迅速增加，部分原因是暴露於空氣汙染的增加。此外，老齡化人口面臨著細菌性肺炎等常見醫院感染的風險增加，這會導致中性粒細胞持續集中到肺部，但導致其清除感染的效果會降低。中性粒細胞的持續炎症反應也是我們最常見的致命性遺傳性疾病之一的囊性纖維化（CF）患者肺功能不斷惡化的主要原因。要想改進這些急性和慢性炎症性疾病的治療方案，更好地了解中性粒細胞在這些肺部疾病中的病理特徵是至關重要的。

HomeostasisLike every tissue in the body, the lung is characterized by a specific immune profile. Circulating neutrophils are retained in the lung microvasculature, forming a reservoir defined as  the lung-marginated neutrophil pool.The use of radiolabeling and adoptive transfer techniques allowed the identification of a marginated neutrophil pool in the capillary bed of the lungs, which was found to be in a dynamic equilibrium with the circulating pool.Several groups have hypothesized that neutrophil margination acts as a protective mechanism to de-prime and sequester activated neutrophils, thus preventing further damage . Recently, supported by the observation that marginated lung neutrophils express the major histocompatibility complex II and interact with B cells in the lung microvasculature, Granton et al. hypothesized that the lung—as with the spleen and liver—may act as an immunological niche. While both theories may support physiological roles to maintain homeostasis and control the immune response, more studies will be needed to elucidate the role for neutrophil margination in the lung microvasculature at steady-state and upon stress responses (Figure 1). The large surface area of the lung environment is indeed constantly exposed to inhaled pathogens and other environmental stimuli, and having abundant neutrophils in the immediate vicinity allows for an efficient and rapid innate immune response.像身體的每一種組織一樣，肺臟具有特殊的免疫特徵。循環中的中性粒細胞保留在肺微血管中，從而形成一個儲存庫，定義為肺邊緣中性粒細胞池。通過使用放射性標記和採用轉移技術，可以在肺毛細血管床中識別出一個有邊際的中性粒細胞池，並且發現它與循環池處於動態平衡狀態。部分研究團隊假設，中性粒細胞邊緣作用作為一種保護機制，啟動和隔離激活的中性粒細胞，從而防止進一步的損害。最近，Granton等人觀察到，肺邊緣中性粒細胞表達組織相容性複合體II，並與肺微血管系統中的B細胞相互作用，這支持了這一觀點。因此他們假設肺像脾臟和肝臟一樣，能夠起到免疫的作用。雖然這兩種理論都可能支持肺邊緣的中性粒細胞在維持穩態和控制免疫反應方面的生理作用，但還需要更多的研究來闡明肺微血管中的邊緣中性粒細胞在穩態和應激反應時的作用(圖1)。大面積的肺環境確實不斷地暴露在吸入病原體和其他環境刺激中，而鄰近大量的中性粒細胞可以產生高效而快速的先天免疫反應。

Stress Response

Unlike some of the longer-lived leukocytes featured in both arms of the immune system,such as mastcells in the innate system and memory T cells and long-lived plasma cells in the adaptive system, neutrophils do not maintain long-term tissue residence. However,they are invaluable for the irability to respond rapidly and in massive manner to almost any type of stress inflicted upon peripheral tissues. The hallmark function of neutrophils is microbial clearance, especially of bacteria, by phagocytosis. It is now well understood how bacteria are captured and digested internally, but neutrophils are also well equipped to clear viruses and fungi, as well as contribute to defenseagainst parasites.與先天免疫系統中的肥大細胞和適應性免疫系統中的記憶T細胞和長壽命血漿細胞等壽命較長的白細胞不同，中性粒細胞在組織內並不能保持長期的停留。然而，它們具備對幾乎任何類型的施加在周圍組織上的刺激都有快速和大規模的反應能力，這是無價的。中性粒細胞的標誌性功能是通過吞噬作用清除微生物，尤其是細菌。目前，非常清楚的是細菌如何在內部被捕獲和消化的，但中性粒細胞也具有清除病毒和真菌的很好的能力，並且有助於防禦寄生蟲。

Neutrophilsin Chronic RespiratoryPathologies

We are now building a greater understanding of how neutrophil responses to infectious challenge,  especially in the lung, are far more complex than simply locating and clearing microbes. Their responsiveness to non-infectious challenge, for example with allergen and smoke exposure, is also a potent factor in innate immune responses. The ability of neutrophils to quickly resolve these challenges  or contribute to pathology has major implications for both organ-specific and systemic health.

In the absence of infection, neutrophilic inflammation can be initiated and result in severe inflammatory pathologies. When neutrophils are recruited to the lungs in the absence of infection, in genetic disorders such as CF, or in diseases linked to environmental conditions such as COPD, they can cause extensive damage through release of their destructive granule contents such as NE and MPO. They also exhibit potent immunomodulatory capabilities whereby they can substantially alter the immune balance of various environments. Inaddition to ongoing tissue damage and altered adaptive immune responses, chronic neutrophilic pathologies are also characterized by neutrophil dysfunction where these cells are not able to effectively conduct their normal duties of debris and microbe clearance. A better understanding of how neutrophilic pathologies are initiated and how they might be corrected is essential for treating patients with rare diseases like CF that currently have few anti-inflammatory treatment options, as well as wide spread diseases like asthma and COPD which are becoming ever-larger public health burdens each year.
我們正在更好地理解中性粒細胞如何應對感染挑戰，尤其是在肺部，而其機理遠比簡單地定位和清除微生物要複雜得多。他們對過敏原和煙霧暴露等非感染性挑戰的強烈反應也是激發先天免疫反應的一個重要因素。中性粒細胞快速處理這些挑戰或促進病理反應發生的能力，對器官特異性和全身健康都有重大影響。
在沒有感染的情況下，中性粒細胞炎症也可能會啟動，並且導致嚴重病理炎症反應的發生。在CF等遺傳性疾病或COPD等與環境條件有關的疾病中，雖沒有感染的發生，中性粒細胞仍然會聚集到肺部，並且通過釋放NE和MPO等破壞性顆粒對肺臟造成廣泛的損害。它們還顯示出強大的免疫調節能力，從而可以極大地改變各種環境的免疫平衡。除了引起持續的組織損傷和改變適應性免疫反應外，慢性病理刺激下的中性粒細胞會引發中性粒細胞功能障礙，從而導致其不能正常、有效地清除碎片和微生物。更好地了解中性粒細胞病理是如何啟動和糾正的，對於治療像CF這樣目前幾乎沒有抗炎治療選擇的罕見疾病，以及像哮喘和COPD這些引發日益沉重的公共衛生負擔的疾病來說是至關重要的。Recent advances in understanding neutrophil biology in health and disease emphasize the plasticity of these cells. Despite comprising the largest proportion of circulating leukocytes, studying the molecular mechanisms of neutrophil function is still a relatively new endeavor in the field of immunology. The identification and clearance of microbes by neutrophils is now well understood, but this represents only a small sample of their functional capabilities. These functional capabilities depend on an array of signaling and effector proteins (Table1).There is now a growing interest in the contribution of neutrophils in chronic disease, especially those relating to the lungs. First, while neutrophilic inflammation has long been known to have a role in CF and COPD, new mechanisms are uncovered by which they may contribute to lung damage. Second, new studies of asthma are shedding light on pathological mechanisms that are driven by a neutrophilic response despite typically being thought of as a type 2-dominated eosinophilic airway disease. Third, considering the monogenic disease CF where the focus has historically been on the mutated CF Transmembrane conductance Regulator ion channel (expressed primarily in epithelial cells), recent studies have indicated that early and sustained neutrophil recruitment to the airways and activation in the mucostatic environment of the CF lung is a major factor in the initiation and progression of lung disease.With our improved understanding of neutrophil contribution to chronic diseases and new data demonstrating metabolic and transcriptional adaptions of neutrophils in these circumstances, neutrophil-directed therapies may soon become an option for the innovative treatment of diseases characterized by chronic neutrophilic inflammation, such as CF and COPD, or acute inflammation such as TRA最近在關於中性粒細胞在健康和疾病生物學的研究中強調其可塑性。儘管中性粒細胞在循環白細胞中所佔比例最大，但對其功能中的分子機制研究在免疫學領域仍是一個相對較新的嘗試。中性粒細胞對微生物的識別和清除現在已經很清楚了，但這僅代表了它們一小部分功能。這些功能依賴於一系列信號和效應蛋白(表1）。現在，人們對中性粒細胞在慢性疾病中的作用越來越感興趣，尤其是那些與肺部有關的疾病。首先，雖然中性粒細胞炎症在CF和COPD中的作用早已為人所知，但發現了導致肺損傷的新的機制。其次，儘管哮喘通常被認為是一種2型主導的嗜酸性氣道疾病，新的研究正在揭示由中性粒細胞反應引發哮喘的病理機制。第三，就單基因疾病CF來說，既往關注的焦點是跨膜電導調節離子通道的變異(主要表達於上皮細胞)，最近的研究表明，早期和持續的中性粒細胞聚集到氣道以及CF肺黏膜抑制環境中的激活是CF肺部疾病發生和發展的主要因素。隨著我們不斷更加深入的了解中性粒細胞在慢性疾病中作用，以及新的數據所顯示的中性粒細胞在這些環境中的代謝和轉錄適應，中性粒細胞導向療法可能很快就會成為CF和COPD等以中性粒細胞慢性炎症為特徵的疾病或TRA等急性炎症的一種創新治療選擇。