Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation.

BACKGROUND: The calcium-binding protein S100A12 is highly up-regulated in the serum and sputum of patients with allergic asthma and is suggested to be a biomarker and pathologic mediator of asthma. OBJECTIVE: To test the role of S100A12 in mediating airway inflammation in a mouse model of allergic lung inflammation. METHODS: Transgenic (TG) mice that express human S100A12 and wild-type (WT) littermates were sensitized and challenged with ovalbumin (OVA) and assessed for inflammation, lung structure, and function. RESULTS: Following OVA sensitization and challenge, S100A12 TG mice showed reduced peribronchial and perivascular inflammation, mucus production, and eosinophilia as well as attenuated airway responsiveness to contractile agonist compared with WT sensitized and challenged animals. This is explained, at least in part, by remodelled airways in S100A12 TG mice with thinning of the airway smooth muscle. S100A12 exposure induced Fas expression and activation of caspase 3 in cultured airway smooth muscle cells, suggesting that airway smooth muscle abnormalities observed in S100A12 TG mice may be mediated through myocyte apoptosis. CONCLUSION AND CLINICAL RELEVANCE: S100A12 is one of the most abundant proteins found in the airways of human asthmatics, and it was postulated that S100A12 could mediate the inflammatory process. Our study shows for the first time that TG expression of S100A12 in the lung of mice does not exacerbate lung inflammation in a model of OVA-induced allergic inflammation. We speculate that the high levels of S100/calgranulins found in bronchoalveolar lavage fluid of asthmatics and of OVA-treated TG S100A12 mice do not significantly mediate pulmonary inflammation.

CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation.

Cell polarization is a key feature of cell motility, driving cell migration to tissues. CD43 is an abundantly expressed molecule on the T-cell surface that shows distinct localization to the migrating T-cell uropod and the distal pole complex (DPC) opposite the immunological synapse via association with the ezrin-radixin-moesin (ERM) family of actin regulatory proteins. CD43 regulates multiple T-cell functions, including T-cell activation, proliferation, apoptosis, and migration. We recently demonstrated that CD43 regulates T-cell trafficking through a phosphorylation site at Ser-76 (S76) within its cytoplasmic tail. Using a phosphorylation-specific antibody, we now find that CD43 phosphorylation at S76 is enhanced by migration signals. We further show that CD43 phosphorylation and normal T-cell trafficking depend on CD43 association with ERM proteins. Interestingly, mutation of S76 to mimic phosphorylation enhances T-cell migration and CD43 movement to the DPC while blocking ERM association, showing that CD43 movement can occur in the absence of ERM binding. We also find that protein kinase CΘ can phosphorylate CD43. These results show that while CD43 binding to ERM proteins is crucial for S76 phosphorylation, CD43 movement and regulation of T-cell migration can occur through an ERM-independent, phosphorylation-dependent mechanism.

Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond.

The first successful human lung transplants were performed in the 1980s. Since that time lung transplantation has been a therapeutic modality for end-stage pulmonary diseases. However, chronic rejection, known as obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), is the key reason why the 5-year survival is only 50%, which is significantly worse than most other solid organ transplants. Recent studies have provided exciting advances that are beginning to be translated into findings in humans. This review will highlight the current advances in understanding the mechanisms of OB/BOS in lung transplant recipients.