IFN-γ-Inducible Protein 10 (CXCL10) Contributes to Airway Hyperreactivity and Airway Inflammation in a Mouse Model of Asthma

Abstract

Allergic asthma is an inflammatory disease of the airways characterized by eosinophilic inflammation and airway hyper-reactivity. Cytokines and chemokines specific for Th2-type inflammation predominate in asthma and in animal models of this disease. The role of Th1-type inflammatory mediators in asthma remains controversial. IFN-γ-inducible protein 10 (IP-10; CXCL10) is an IFN-γ-inducible chemokine that preferentially attracts activated Th1 lymphocytes. IP-10 is up-regulated in the airways of asthmatics, but its function in asthma is unclear. To investigate the role of IP-10 in allergic airway disease, we examined the expression of IP-10 in a murine model of asthma and the effects of overexpression and deletion of IP-10 in this model using IP-10-transgenic and IP-10-deficient mice. Our experiments demonstrate that IP-10 is up-regulated in the lung after allergen challenge. Mice that overexpress IP-10 in the lung exhibited significantly increased airway hyperreactivity, eosinophilia, IL-4 levels, and CD8+ lymphocyte recruitment compared with wild-type controls. In addition, there was an increase in the percentage of IL-4-secreting T lymphocytes in the lungs of IP-10-transgenic mice. In contrast, mice deficient in IP-10 demonstrated the opposite results compared with wild-type controls, with a significant reduction in these measures of Th2-type allergic airway inflammation. Our results demonstrate that IP-10, a Th1-type chemokine, is up-regulated in allergic pulmonary inflammation and that this contributes to the airway hyperreactivity and Th2-type inflammation seen in this model of asthma.

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6

“…In addition, we demonstrated that ORMDL3 selectively regulates activation of the ER localized transcription factor ATF6α signaling branch, a pathway we have demonstrated in human lung epithelial cells is linked to SERCA-2b, which is implicated in airway remodeling in asthma (24). Finally, our studies demonstrate that ORMDL3 activates several metalloprotease, chemokine, and OAS-regulated genes, several of whom have also been implicated in the pathogenesis of asthma (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Overall, these studies provide evidence for a mechanism to link an ER localized protein such as ORMDL3 to the pathogenesis of asthma.…”

“…The importance of these ORMDL3-regulated genes to asthma is suggested from studies demonstrating increased expression of many of these mediators in the airways of human asthmatics (MMP-9, ADAM-8, CCL-20, CXCL-10, IL-8) (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), induction of these mediators by allergen inhalation in asthmatics (MMP-9, CCL-20, CXCL-10) (7,12,19), and inhibition of asthma outcomes in mice deficient in these genes (MMP-9, ADAM-8, CXCL-10) (8,9,11,20,21). In addition to the important role of CCL-20 on T-cell recruitment (12), and epithelial mucus production (14), in mouse models of asthma, there is a critical link between CCL-20 and TRAIL for Th2 cell activation and allergic airway inflammation (15).…”

“…In addition to the important role of CCL-20 on T-cell recruitment (12), and epithelial mucus production (14), in mouse models of asthma, there is a critical link between CCL-20 and TRAIL for Th2 cell activation and allergic airway inflammation (15). Although asthma has predominantly been associated with expression of CC chemokines, both CC and CXC chemokines have been linked to asthma in studies in humans with asthma (12,13,(16)(17)(18)(19), and in studies in animal models (13, 20, 21) (i.e., CXCL-10 KO have significant reduction in Th2-type allergic airway inflammation and AHR) (20). In addition to identifying genes linked to asthma, the transfection of ORMDL3 into human bronchial epithelial cells also induced expression of OAS genes (31), a pathway not previously linked to ORMDL3.…”

“…We have made the unique observation that ORMDL3 is an allergen (and Th2 cytokine) inducible STAT-6-dependent gene expressed in the lung, in particular in airway epithelial cells. In addition, we demonstrate that transfection of ORMDL3 into normal human lung bronchial epithelial cells induces expression of genes with potential importance to the pathogenesis of asthma including metalloproteases (MMP-9 and ADAM-8) (7-11), CC chemokines (CCL-20 also known as MIP-3α) (12)(13)(14)(15), CXC chemokines (IL-8 and CXCL-10) (16)(17)(18)(19)(20)(21), and oligoadenylate synthetases (OAS) anti-viral regulated genes not previously implicated in asthma. Finally, we demonstrate that ORMDL3 transfection in lung epithelial cells activates the ATF6 pathway, one of three branches of the ER localized unfolded protein response (22,23), whereas siRNA knockdown of ATF-6 in lung epithelial cells inhibited expression of SERCA2b (sarco/ endoplasmic reticulum Ca 2+ ATPase), which has been implicated in remodeling in asthma (24).…”

Metal composition of ambient PM2.5 influences severity of allergic airways disease in mice.

“…Therefore, it is somewhat surprising that IFN-γ levels were increased in BAL fluid of mice exposed to both Hettstedt and Zerbst PM 2.5 , while airway hyperresponsiveness, OVA-specific IgE, and BAL eosinophils were increased in the Hettstedt PM 2.5 -exposed group. However, recent studies indicate that IFN-γ induces the production of the chemokine CXCL10, which promotes allergic inflammation and airway hyperresponsiveness in mice (Medoff et al 2002). Therefore, IFN-γ has dual roles, and both TNF-α and IFN-γ may contribute to allergic inflammation and airway hyperresponsiveness observed in mice exposed to Hettstedt PM 2.5 .…”