Abstract
Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev) mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs) were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13), chemokines (eotaxin), and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.
Highlights
Encountering exogenous antigens and pathogens from the environment, upper and lower airways form an effective defense while maintaining tolerance to self-antigens [1]
Various levels of IFN-c were found in sinus lavage samples [7] and few studies have examined the direct effects of IFN-c on eosinophilic inflammation in allergic rhinitis and chronic rhinosinusitis [8]
Spontaneous eosinophilic rhinitis in mev mice First, we compared the cytology of the nasal airway lavage (NAL) fluids and nasal histopathology of WT and mev mice (Figure 1A, 1B)
Summary
Encountering exogenous antigens and pathogens from the environment, upper and lower airways form an effective defense while maintaining tolerance to self-antigens [1]. This mucosal immune homeostasis can become dysregulated, resulting in skewed immune responses, such as T cell mediated Th1, Th2, or Th17 responses. Allergic rhinitis and chronic rhinosinusitis with polyposis are examples of persistent inflammatory diseases of the upper airway dominated by CD4+ Th2 effector cells secreting IL4, IL-5, and IL-13 in response to commonly inhaled antigens [2,3,4]. Various levels of IFN-c were found in sinus lavage samples [7] and few studies have examined the direct effects of IFN-c on eosinophilic inflammation in allergic rhinitis and chronic rhinosinusitis [8]
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