Abstract
Allergic airway inflammation is driven by type-2 CD4+ Tcell inflammatory responses. We uncover an immunoregulatory role for the nucleotide release channel, Panx1, in Tcell crosstalk during airway disease. Inverse correlations between Panx1 and asthmatics and our mouse models revealed the necessity, specificity, and sufficiency of Panx1 in Tcells to restrict inflammation. Global Panx1-/- mice experienced exacerbated airway inflammation, and T-cell-specific deletion phenocopied Panx1-/- mice. A transgenic designed to re-express Panx1 in Tcells reversed disease severity in global Panx1-/- mice. Panx1 activation occurred in pro-inflammatory T effector (Teff) and inhibitory T regulatory (Treg) cells and mediated the extracellular-nucleotide-based Treg-Teff crosstalk required for suppression of Teff cell proliferation. Mechanistic studies identified a Salt-inducible kinase-dependent phosphorylation of Panx1 serine 205 important for channel activation. A genetically targeted mouse expressing non-phosphorylatable Panx1S205A phenocopied the exacerbated inflammation in Panx1-/- mice. These data identify Panx1-dependent Treg:Teff cell communication in restricting airway disease.
Highlights
Allergic airway inflammation, known as allergic asthma, affects approximately 1 in 20 individuals or about 300 million people worldwide (Lambrecht and Hammad, 2015)
Pannexin 1 (Panx1)–/– mice exhibit exacerbated allergen-induced airway inflammation When we examined human datasets for PANX1 expression in asthmatic patients (Raedler et al, 2015), we noted that PANX1 expression was significantly reduced in the peripheral blood mononuclear cells (PBMCs) of allergic asthmatic children, relative to healthy controls (Figure 1A)
To directly investigate the importance of Panx1 in airway disease, we used wild-type and Panx1-deficient mice in a model of allergic airway inflammation induced by housedust mite (HDM), a relevant pathologic allergen in developed countries (Arias-Calderon et al, 2016; Gandhi et al, 2013; Gold et al, 2015)
Summary
Known as allergic asthma, affects approximately 1 in 20 individuals or about 300 million people worldwide (Lambrecht and Hammad, 2015). Th2 CD4+ T cells that infiltrate the lungs produce interleukin-4 (IL-4) and IL-5 to mediate eosinophilia, immunoglobulin E (IgE) accumulation, mast-cell degranulation, and bronchial hyperreactivity (Walker et al, 1991) While treatments such as inhaled corticosteroids can alleviate the inflammatory symptoms of disease, many patients are still refractory to such therapeutics (Umetsu and DeKruyff, 2006). Among the many cellular and acellular factors contributing to disease progression and severity, extracellular ATP (eATP) is one dynamic signaling molecule found in the bronchoalveolar lavage of asthmatic patients (Lazar et al, 2010) Both inflammatory and immunosuppressive roles for extracellular ATP during allergic airway inflammation have been described (Idzko et al, 2013). The actions of extracellular ATP and their metabolic breakdown products have been described, the source and specific cellular contributions for these extracellular nucleotides in different disease settings, including allergic airway inflammation, are unknown
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