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ACKR2 contributes to pulmonary dysfunction by shaping CCL5:CCR5-dependent recruitment of lymphocytes during Influenza A infection in mice.

ACKR2 通过塑造 CCL5 导致肺功能障碍: CCR5-dependent 小鼠甲型流感感染时淋巴细胞的募集。

  • 影响因子:3.82
  • DOI:10.1152/ajplung.00134.2019
  • 作者列表:"Tavares LP","Garcia CC","Gonçalves APF","Kraemer LR","Melo EM","Oliveira FMS","Freitas CS","Lopes GAO","Reis DC","Cassali GD","Machado AM","Mantovani A","Locati M","Teixeira MM","Russo RC
  • 发表时间:2020-01-29

RATIONALE:Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses and return to lung homeostasis. However, an exaggerated immune response, characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC-chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. OBJECTIVE:We investigated the role of ACKR2 during IAV infection in mice. RESULTS:Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2-/-) mice were protected from IAV presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B-lymphocytes, formation of iBALT and production of IgA in the airways of ACKR2-/- mice post-IAV. CCL5 neutralization in ACKR2-/- mice prevented lymphocyte recruitment and increased BALF protein levels and pulmonary dysfunction. Finally, CCR5-/- mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. CONCLUSION:Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5+ Th1, Treg and B-lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice.


原理: 甲型流感病毒 (IAV) 感染引发的炎症对病毒清除、诱导适应性反应和恢复肺稳态很重要。然而,过度的免疫反应,其特征在于趋化因子的过度产生,可导致强烈的肺损伤,导致死亡率。趋化因子清道夫受体,如 ACKR2,控制影响免疫反应的 CC-趋化因子的水平。在 ACKR2 的趋化因子靶点中,CCL5 重要招募和激活淋巴细胞。 目的: 研究 ACKR2 在小鼠 IAV 感染中的作用。 结果: 在病毒引起的肺功能障碍之前,IAV 感染后肺 ACKR2 表达急剧增加。ACKR2-knockout (ACKR2-/-) 小鼠免受 IAV 出现病毒负荷降低和肺功能障碍的影响。机械上,ACKR2 的缺失导致气道 CCL5 水平升高,由肺实质中的单核细胞和浆细胞分泌。较高的趋化因子梯度导致 IAV 后 ACKR2-/-小鼠气道中 T 和 B 淋巴细胞募集增加,iBALT 形成和 IgA 产生增加。ACKR2-/-小鼠 CCL5 中和可防止淋巴细胞募集,增加 BALF 蛋白水平和肺功能障碍。最后,CCR5-/-小鼠在 IAV 感染过程中呈现疾病严重程度增加,显示中性粒细胞增加,肺损伤和功能障碍,并加重致死率。 结论: 总的来说,我们的数据显示,ACKR2 在 IAV 感染过程中抑制了 CCL5 水平以及随之而来的 CCR5 + Th1 、 Treg 和 B 淋巴细胞的募集, 减少病原体控制,促进野生型小鼠肺功能障碍。因此,ACKR2 是有害的,CCR5 在 IAV 感染过程中具有保护性,协调小鼠的固有免疫和适应性免疫反应。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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