IL-1β prevents ILC2 expansion, type 2 cytokine secretion and mucus metaplasia in response to early-life rhinovirus infection in mice.
Il-1 β 可防止 ILC2 扩增、 2 型细胞因子分泌和粘液化生，以应对小鼠早期鼻病毒感染。
- 作者列表："Han M","Ishikawa T","Bermick JR","Rajput C","Lei J","Goldsmith AM","Jarman CR","Lee J","Bentley JK","Hershenson MB
BACKGROUND:Early-life wheezing-associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of six day-old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL-13-producing type 2 innate lymphoid cells (ILC2s) and dependent on IL-25 and IL-33. We examined regulation of this asthma-like phenotype by IL-1β. METHODS:Six day-old wild type or NRLP3-/- mice were inoculated with sham or RV-A1B. Selected mice were treated with IL-1 receptor antagonist (IL-1RA), anti-IL-1β or recombinant IL-1β. RESULTS:RV infection induced Il25, Il33, Il4, Il5, Il13, muc5ac and gob5 mRNA expression, ILC2 expansion, mucus metaplasia and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro-IL-1β and NLRP3 as well as cleavage of caspase-1 and pro-IL-1β, indicating inflammasome priming and activation. Lung macrophages were a major source of IL-1β. Inhibition of IL-1β signaling with IL-1RA, anti-IL-1β or NLRP3 KO increased RV-induced type 2 cytokine immune responses, ILC2 number and mucus metaplasia, while decreasing IL-17 mRNA expression. Treatment with IL-1β had the opposite effect, decreasing IL-25, IL-33 and mucous metaplasia while increasing IL-17 expression. IL-1β and IL-17 each suppressed Il25, Il33 and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RV-infected 6 day-old mice showed reduced IL-1β mRNA and protein expression compared to mature mice. CONCLUSION:Macrophage IL-1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL-1β production in immature animals provides a mechanism permitting asthma development after early-life viral infection.
背景: 早期喘息相关的人类鼻病毒 (RV) 呼吸道感染与哮喘的发展相关。6 日龄未成熟小鼠的 RV 感染引起黏液化生和气道高反应性，这与 IL-13-producing 2 型固有淋巴细胞 (ILC2s) 的扩增有关，并依赖于 IL-25 和 IL-33。我们检测了 il-1 β 对这种哮喘样表型的调控。 方法: 6 日龄野生型或 NRLP3-/-小鼠接种假或 RV-A1B。选择小鼠用 IL-1 受体拮抗剂 (IL-1RA) 、抗 il-1 β 或重组 il-1 β 治疗。 结果: RV 感染诱导 Il25 、 Il33 、 Il4 、 Il5 、 Il13 、 muc5ac 和 gob5 mRNA 表达，ILC2 扩张，黏液化生和气道高反应性。RV 还可诱导肺中 il-1 β 和 NLRP3 的 mRNA 和蛋白表达，以及 caspase-1 和 il-1 β 的裂解，表明炎症小体启动和激活。肺巨噬细胞是 il-1 β 的主要来源。用 IL-1RA 、抗 il-1 β 或 NLRP3 KO 抑制 il-1 β 信号增加 RV 诱导的 2 型细胞因子免疫反应、 ILC2 数量和粘液化生，同时降低 IL-17 mRNA 表达。用 il-1 β 治疗的效果相反，降低 IL-25，IL-33 和粘液化生，同时增加 IL-17 表达。Il-1 β 和 IL-17 均可抑制培养的气道上皮细胞 Il25 、 Il33 和 muc5ac mRNA 的表达。最后，与成熟小鼠相比，RV 感染的 6 日龄小鼠表现出 il-1 β mRNA 和蛋白表达降低。 结论: 巨噬细胞 il-1 β 通过抑制上皮细胞固有细胞因子的表达，限制 RV 感染后的 2 型炎症和黏液化生。未成熟动物 il-1 β 产生减少提供了一种机制，允许早期病毒感染后发生哮喘。
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.
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.
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.