Immune Modulatory Effects of IL-22 On Allergen-Induced Pulmonary Inflammation

Ping Fang

doi:10.1016/j.jaci.2012.12.1351

Abstract

RationaleAllergen-induced pulmonary inflammation in asthma is mainly TH2 dominated. A recently discovered TH17/TH22 cell-derived cytokine, IL-22, has been found to be increased in asthma. However, several studies showed controversial findings in the immune modulatory effects of IL-22 in animal models of allergic asthma. Our objective was to determine the regulatory role of IL-22 in OVA-induced allergic inflammation using a novel lung-specific IL-22 transgenic overexpression system.MethodsInducible IL-22 transgenic (CC10-rtTA- and SPC-rtTA-TRE-tight-IL-22) mice on C57BL/6 genetic background were generated. IHC of lung tissue and ELISA of bronchoalveolar lavage (BAL) fluid for IL-22 were performed to confirm the location and quantity of IL-22 expression. OVA-induced pulmonary inflammatory responses were compared between IL-22 transgenic and wild type control mice. BAL total and differential cell counts, lung histology, mucous metaplasia, IHC of major basic protein for eosinophils, and serum OVA-specific IgE were determined.ResultsIL-22 transgene was successfully activated in the large (CC10 promoter) and small (SPC promoter) airway epithelium cells by doxycycline in the drinking water. OVA sensitization and challenge did not induce endogenous IL-22 expression. Compared to wild type mice, IL-22 transgenic mice showed decreased percentage of eosinophils in the BAL and slight reduction in eosinophilic inflammation and mucus metaplasia in the airways. Interestingly, inflammatory cell infiltration in lung parenchyma appeared slightly accentuated. In addition, there was no statistic difference in serum OVA-specific IgE.ConclusionsThese findings indicate that IL-22 may have immune modulatory effects on pulmonary inflammatory responses in the development of allergen-induced asthma. RationaleAllergen-induced pulmonary inflammation in asthma is mainly TH2 dominated. A recently discovered TH17/TH22 cell-derived cytokine, IL-22, has been found to be increased in asthma. However, several studies showed controversial findings in the immune modulatory effects of IL-22 in animal models of allergic asthma. Our objective was to determine the regulatory role of IL-22 in OVA-induced allergic inflammation using a novel lung-specific IL-22 transgenic overexpression system. Allergen-induced pulmonary inflammation in asthma is mainly TH2 dominated. A recently discovered TH17/TH22 cell-derived cytokine, IL-22, has been found to be increased in asthma. However, several studies showed controversial findings in the immune modulatory effects of IL-22 in animal models of allergic asthma. Our objective was to determine the regulatory role of IL-22 in OVA-induced allergic inflammation using a novel lung-specific IL-22 transgenic overexpression system. MethodsInducible IL-22 transgenic (CC10-rtTA- and SPC-rtTA-TRE-tight-IL-22) mice on C57BL/6 genetic background were generated. IHC of lung tissue and ELISA of bronchoalveolar lavage (BAL) fluid for IL-22 were performed to confirm the location and quantity of IL-22 expression. OVA-induced pulmonary inflammatory responses were compared between IL-22 transgenic and wild type control mice. BAL total and differential cell counts, lung histology, mucous metaplasia, IHC of major basic protein for eosinophils, and serum OVA-specific IgE were determined. Inducible IL-22 transgenic (CC10-rtTA- and SPC-rtTA-TRE-tight-IL-22) mice on C57BL/6 genetic background were generated. IHC of lung tissue and ELISA of bronchoalveolar lavage (BAL) fluid for IL-22 were performed to confirm the location and quantity of IL-22 expression. OVA-induced pulmonary inflammatory responses were compared between IL-22 transgenic and wild type control mice. BAL total and differential cell counts, lung histology, mucous metaplasia, IHC of major basic protein for eosinophils, and serum OVA-specific IgE were determined. ResultsIL-22 transgene was successfully activated in the large (CC10 promoter) and small (SPC promoter) airway epithelium cells by doxycycline in the drinking water. OVA sensitization and challenge did not induce endogenous IL-22 expression. Compared to wild type mice, IL-22 transgenic mice showed decreased percentage of eosinophils in the BAL and slight reduction in eosinophilic inflammation and mucus metaplasia in the airways. Interestingly, inflammatory cell infiltration in lung parenchyma appeared slightly accentuated. In addition, there was no statistic difference in serum OVA-specific IgE. IL-22 transgene was successfully activated in the large (CC10 promoter) and small (SPC promoter) airway epithelium cells by doxycycline in the drinking water. OVA sensitization and challenge did not induce endogenous IL-22 expression. Compared to wild type mice, IL-22 transgenic mice showed decreased percentage of eosinophils in the BAL and slight reduction in eosinophilic inflammation and mucus metaplasia in the airways. Interestingly, inflammatory cell infiltration in lung parenchyma appeared slightly accentuated. In addition, there was no statistic difference in serum OVA-specific IgE. ConclusionsThese findings indicate that IL-22 may have immune modulatory effects on pulmonary inflammatory responses in the development of allergen-induced asthma. These findings indicate that IL-22 may have immune modulatory effects on pulmonary inflammatory responses in the development of allergen-induced asthma.

Highlights

Allergen-induced pulmonary responses in asthma are characterized by eosinophil infiltration, mucus hypersecretion, airway hyperreactivity and bronchoconstriction
After Dox induction for 4 weeks, IL-22 mRNA was readily detected in the lung tissue and IL-22 protein was elevated in the bronchoalveolar lavage (BAL) fluid of Tg(+) mice but not in Tg(2) mice by ELISA (Figure 1A, 1B)
Recent studies suggested that Th17/ Th22 cytokines IL-17 and IL-22 have regulatory effects on allergic airway inflammation

Summary

Introduction

Allergen-induced pulmonary responses in asthma are characterized by eosinophil infiltration, mucus hypersecretion, airway hyperreactivity and bronchoconstriction. The Th17 cytokine IL-17A is critical in the pathogenesis of severe asthma [4,5]. A novel Th17/Th22 cytokine, IL22, was found to have immune modulatory effects on pulmonary allergic inflammation [6,7,8]. Th17/Th22 cells mainly secrete IL-17A, IL-17F and IL-22 [9,10] Both IL-17 and IL-22 have been found to have a major impact in epithelial cells in various tissues and are key regulators of homeostasis and epithelial barrier function. The immune modulatory effects of IL-22 in allergen-induced lung inflammation are not well understood

Methods

Results

Conclusion