JEM Zhou Jie/Yao Zhi of Tianjin Medical University Reveal the Important Role of Lung renin Angiotensin System in Asthma

iNature type II innate lymphoid cells (ILC2s) have emerged as key mediators driving allergic airway inflammation
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However, the detailed mechanism of action remains unclear
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On March 7, 2022, Zhou Jie and Yao Zhi from Tianjin Medical University jointly published a research paper entitled "Angiotensin II enhances group 2 innate lymphoid cell responses via AT1a during airway inflammation" in the Journal of Experimental Medicine (IF=14).
, which identified angiotensin (Ang) II as a positive regulator of ILC2
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ILC2s express higher levels of the angiotensin II receptor AT1a and coexist with angiotensinogen-expressing lung epithelial cells
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Administration of angiotensin-converting enzyme II significantly enhanced ILC2 responses in vivo and in vitro, which were almost completely abolished in AT1a-deficient mice
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AT1a deletion or pharmacological inhibition of the Ang II-AT1 axis significantly alleviated airway inflammation
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Regulation of ILC2s by Ang II is cell-intrinsic, IL-33-dependent, and associated with marked changes in transcriptional profiles and upregulation of ERK1/2 phosphorylation
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In addition, elevated plasma Ang II levels in asthma patients were positively correlated with the abundance of circulating ILC2s and disease severity
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In conclusion, this study reveals a critical role for Ang II in regulating ILC2 responses and airway inflammation
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Allergic asthma is caused by repeated exposure to allergens and is one of the most common chronic inflammatory diseases
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Airway hyperresponsiveness and airway remodeling are the main pathological basis of this disease
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Type 2 T helper cells (Th2)-mediated production of IgE by B cells and recruitment of mast cells and eosinophils are thought to be the main mechanisms of allergic asthma
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Emerging evidence suggests that type II innate lymphoid cells (ILC2s) are important in both initiating and amplifying allergic airway inflammation
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During allergen challenge and helminth infection, lung epithelial cells secrete certain hormones, such as IL-33, IL-25, and thymic stromal lymphopoietin, that activate ILC2s that reside in the lungs and trigger their secretion of the type 2 cytokine IL -5 and IL-13
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These cascades lead to eosinophil recruitment, goblet cell proliferation, and Th2 activation, ultimately leading to allergic airway inflammation
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Therefore, ILC2 is considered to be one of the main drivers of type 2 allergic inflammation
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Unlike Th2 cells in adaptive immunity, ILC2 cells do not express antigen-specific receptors; their activation is immediate and does not involve antigen presentation
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The regulatory mechanism of ILC2 has been extensively studied
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ILC2s express receptors, including receptors for certain cytokines, lipid mediators, neurotransmitters, hormones, and nutrients, which make them highly responsive to various stimuli from the tissue microenvironment
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ILC2s also express receptors and ligands that mediate cell-to-cell interactions
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When receiving tissue-derived stimuli through specific receptors, ILC2s can be rapidly activated or inhibited, thereby altering tissue homeostasis or triggering inflammation
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Important role of lung epithelial cell-derived soluble factors in regulating ILC2 responses in allergic airway inflammation
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However, the molecular mechanisms by which lung epithelial-derived peptides regulate ILC2s are only partially understood
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Clinical significance of angiotensin II in asthma patients (image courtesy of Journal of Experimental Medicine) In this study, it was found that lung epithelial cells markedly induce Ang II synthesis upon allergen challenge
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ILC2 cells express the angiotensin II receptor AT1a
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This study demonstrates that Ang II promotes ILC2 responses in a cellular endogenous and IL-33-dependent manner
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Deletion of AT1a or pharmacological inhibition of the Ang II-AT1 axis significantly reduced allergic airway inflammation
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The level of Ang II in peripheral blood of asthmatic patients was higher than that of healthy people, and it was positively correlated with the proportion of ILC2
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Taken together, these findings provide new insights into the regulatory mechanisms of ILC2 during airway inflammation
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Reference message: https://doi.
org/10.
1084/jem.
20211001