Viral Stimuli Trigger Exaggerated Thymic Stromal Lymphopoietin Expression by Chronic Obstructive Pulmonary Disease Epithelium: Role of Endosomal TLR3 and Cytosolic RIG-I-Like Helicases

Abstract

Background: Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH₂-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH₂-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. Methods: Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5–5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1–10 µg/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1–10 µg/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). Results: dsRNA dose-dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-α in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-β induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-α, and IFN-β. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-α, and IFN-β, but not TSLP. Conclusions: Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA- and RV-induced overproduction of TNF-α and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-β in COPD-BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD.

Nod-Like Receptor X-1 Is Required for Rhinovirus-Induced Barrier Dysfunction in Airway Epithelial Cells

“…Recently, Nod-like receptor X-1 (NLRX-1) has also been shown to recognize dsRNA and to inhibit RIG-I like receptorstimulated interferon responses (13)(14)(15). RV has been shown to induce antiviral interferon responses in airway epithelial cells via TLR3, PKR, RIG-I, and MDA-5 (16)(17)(18)(19). RV has also been shown to stimulate chemokine expression and mucin gene expression by activating TLR3 (20)(21)(22).…”

Epithelial Cell Regulation of Immune Responses in the Lung

“…Airway ECs from smokers or from patients with chronic obstructive pulmonary disease (COPD), a chronic lung disorder punctuated by viral-induced exacerbations, show increased production of TSLP when exposed to rhinovirus, compared to normal cells (Calven et al;Horvath et al, 2011).…”

The role of infection in the pathogenesis of allergodermatoses

“…Уровень фактора в крови взрослых больных АтД может варьировать [26,27]. Роль ТСЛП также показана при астме, различных атопических заболе-ваниях, хронической обструктивной болезни легких [28][29][30][31].…”

“…Показано, что эпителиальные клетки вы-свобождают ТСЛП в ответ на активацию Toll-подобных рецепторов (TLR2, 3, 4, 8, 9) такими ли-гандами, как двухцепочечная РНК вирусов, polyI:C, пептидогликанами и липотехоевой кислотой; poly(CpG) нуклеотидами; липополисахаридом и другими [30,[32][33][34], что практически перекрывает весь спектр распознаваемых иммунной системой молекул патогенов, часто выявляемых на коже боль-ных с АтД.…”