FSTL1 Induces The Activation Of ILC2 Through MEK/JAK-STATs Pathway To Promote Airway Inflammation In Asthma

BackgroundBronchial asthma is a heterogeneous disease.According to the clusters of demographic,clinical and pathophysiological characteristics,Asthma is divided into several common ’asthma phenotypes’,such as:allergic asthma,non-allergic asthma,late-onset asthma,asthma with fixed airflow limitation and asthma with obesity,and allergic asthma is the most common asthma phenotype of bronchial asthma.Recently,more and more studies have found that group 2 innate lymphoid cells(ILC2)play an important role in the development of allergic diseases,such as bronchial asthma,allergic rhinitis,allergic dermatitis and chronic rhinosinusitis with nasal polyps(CRSwNP).ILC2 are recently defined as lymphocyte subsets,which are known to lack T-and B-cell antigen receptors and lymphoid and myeloid lineage markers,and they can contribute to the development of asthma by mediating innate immunity.ILC2 arise from common lymphatic progenitors(CLPs)in the Fetal liver and hematopoietic stem cells,and controlled by the transcription factor RORa.GATA3.When environmental allergens,proteases and virus are encountered by epithelial cells,ILC2s respond to Epithelial cell-derived cytokines IL-25,IL-33,or TSLP immediately,and produce abundant Th2-type cytokines,namely IL-4,IL-5,and IL-13.IL-4 induces IgE production by B cells,which can bind to high affinity Fc ￡receptors(Fc ε RI)on mast cells and basophils.IL-5 activates eosinophils and attractsthem to the lung,where they secrete numerous inflammatory cytokines and chemokines.IL-13 directly affects the airway epithelium and smooth muscle cells in the lungs and thereby contributes to AHR,mucus hyperproduction,and,in persistent inflammation,to airway remodeling.Besidies,many cytokines and lipid mediators can regulate ILC2 in human allergic airway disease.Follistatin-like protein 1(FSTL1)is a new pro-inflammatory cytokine,it can play a pro-inflammatory response by ERK1/2、IKKβ、IKBα、JNK and NF-Kβ signaling pathways and et al.FSTL1 participate in a variety of biological processes,including cell proliferation,apoptosis,metabolism,differentiation,immune response and endocrine function.In addition,its expression changes with respect to its level and pattern during various diseases,including cardiovascular disease,cancer progression,systemic autoimmune diseases and also respiratory system disease.The expression of FSTL1 in airway tissue,bronchoalveolar Lavage Fluid and peripheral blood of asthmatic patients was increased than healthy control,and the expression level was positive correlated with the severity of asthma.Based on the latest studies at home and abroad,we speculate that FSTL1 can also induce the activation of ILC2s and promote airway inflammation in asthma patients,and in this research we will study on this to find new targets for the treatment of asthma.ObjectiveTo investigate the mechanism of FSTL1 inducing ILC2s activation and promoting airway inflammation in asthma patients.MethodsC57BL/6 mice and FSTL1+/-mice were sensitized with OVA to eatablish the asthma model,and the control groups were sensitized and challenged with PBS only We divided these mouse into four groups,WT mice-OVA-challenged and WT mice-control group,FSTL1+/--OVA-challenged and FSTL1+/--control group.In order to study the underlying mechanism of FSTL1 inducing ILC2 activation and promoting airway inflammation in asthma,we used some experimental techniques in this research,such as Flow cytometry(FCM),Western Blot,H&E staining,immunohistochemical staining,and et al.Results1.FSTL1 can promote airway inflammation in asthma.H&E staining showed that the number of inflammatory cells around the airway tissue of FSTL1+/-asthmatic mice was lower than WT asthmatic mice,and the inflammatory response was weakened.2.FSTL1 can promote the increase of ILC2.The proportion of ILC2 in the lung and spleen of FSTL1+/-asthmatic mice was lower than WT asthmatic mice.After ILC2 sorting and then cultured in vitro,the number of ILC2 which stimulated by FSTL1 was increased than the control group.3.FSTL1 promotes airway inflammation in asthma by inducing the activation of ILC2.The levels of Th2-types cytokines IL-4,IL-5 and IL-13 in the bronchoalveolar lavage fluid and serum of FSTL1+/-asthmatic mice and WT asthmatic mice were both increased compared with the control group.In addition,the cytokines IL-4,IL-5,IL-13 levels in bronchoalveolar lavage fluid and serum of FSTL1+/-asthmatic mice were decreased than the WT asthmatic mice.4.FSTL1 can induce the activation of ILC2 by MEK/JAK-STAT signaling pathway and then result in asthma airway inflammation.After FSTL1 stimulation,the expression of relevant indicators in MEK/JAK-STAT signaling pathway was increased and the levels of Th2-types cytokines IL-4,IL-5 and IL-13 were increased either,but when they were stimulated by the inhibitors of signaling pathway,the levels of Th2-types cytokines IL-4,IL-5 and IL-13 were decreased.ConclusionFSTL1 can induce the activation of ILC2 by MEK/JAK-STAT signaling pathway and then result in asthma airway inflammation.