Downregulation Of STING Contributes To Eosinophilia In Airways By Promoting CCL26 Production In Epithelial Cells

Background:Stimulator of interferon genes(STING),an intracellular receptor that senses pathogen-derived or abnormal self-DNA in the cytosolic,has important roles functions in the host defense against microbial infection and autoimmune diseases.However,the pathophysiological relevance of stimulator of interferon genes(STING)in airway inflammatory conditions including chronic rhinosinusitis(CRS)and asthma remains largely unknownObjective:To explore the expression,regulation,and function of STING in mucosa airway diseases.Methods:STING expression in the sinonasal mucosa was analyzed by means of quantitative RT-PCR,immunohistochemistry,immunofluorescence,flow cytometry,and western blotting.Human primary nasal epithelial cells(HNECs)were cultured and treated with various cytokines and TLRs agonists.In some experiments,BEAS-2B cells and HNECs were transfected with STING or suppressor of cytokine signaling(SOCS)1 small interfering RNA(siRNA)or STING overexpressing plasmids and treated with interleukin(IL)-13 in the presence or absence of 2’3’-cGAMP treatment.Bronchial brushings from controls and asthmatics were subjected to quantitative RT-PCRResults:STING mRNA and protein expression were reduced in eosinophilic nasal polyp compared with non-eosinophilic nasal polyp and control tissues.STING was predominantly expressed by epithelial cells in sinonasal mucosa.T-helper(Th)type-2 cytokines,but not Thl or Th17 cytokines,downregulate STING in HNECs.HNECs from eosinophilic CRSwNP displayed diminished 2’3’-cGAMP-induced type Ⅰ interferons,while enhanced IL-13-mediated chemokine ligand(CCL)26 production compared with non-eosinophilic CRSwNP and controls.Overexpressing STING inhibits CCL26 production in HNECs from eosinophilic CRSwNP.Knocking down or overexpressing STING determines SOCS1 expression in BEAS-2B cells.STING expression positively correlated with SOCS1 expression in HNECs.STING expression was also decreased in bronchial brushings from eosinophilic asthma patients and negatively correlated with CCL26 expression in bronchial brushings and eosinophil percentage in induced sputumConclusion:Patients with eosinophilic CRSwNP and asthma have reduced STING expression in airway epithelial cells.Downregulation of STING expression caused by type-2 milieu enhanced IL-13-induced CCL26 production by regulating SOCS1 expression in nasal epithelial cells,suggesting a novel role in regulating eosinophilic inflammation in airways diseasesClinical implication: Defective STING expression may result in exaggerating eosinophil infiltration in CRSw NP and asthma.Effective strategies can be designed to target STING to inhibit tissue eosinophilia.Capsule summary: Expression of STING in epithelial cells can be downregulated by type-2 cytokines.STING contributes to airway eosinophilic inflammation by modulating the production of CCL26 via regulating SOCS1 expression.