Gwinn WM, Damsker JM, Falahati R, et al. J Immunol. 2006;177:4870–4879

PURPOSE OF THE STUDY. Extracellular cyclophilins are known to promote chemotaxis of various leukocyte subsets through interaction with the cell surface signaling receptor CD147. Increased levels of extracellular cyclophilins have been reported in various inflammatory diseases. This study investigated whether extracellular cyclophilin-CD147 interaction plays a role in the recruitment of leukocytes in asthmatic lung inflammation.

METHODS. A mouse model of allergic asthma was created by intraperitoneal ovalbumin injection into newborn mice, followed by intranasal ovalbumin challenge on days 7 to 10. For in vivo inhibition studies, anti-CD147 was administered intraperitoneally on days 6 to 11. Bronchial hyperreactivity was assessed on day 12. After sacrifice on day 12, the following were examined: histology on bronchoalveolar lavage (BAL) and lung biopsy, cytokine levels after restimulation of pulmonary lymphocytes with ovalbumin antigen, cyclophilin (Cyp) A and CypB levels in BAL fluid by Western blot analysis, chemotaxis of eosinophils and CD4+ splenocytes to CypA and CypB, and CD147 expression levels on CD4+ T cells by fluorescence-activated cell sorter analysis.

RESULTS. The mouse model of asthma-mediated lung inflammation was confirmed by the findings of elevated eosinophils and lymphocytes in the BAL of ovalbumin mice, elevated interleukin 5 (IL-5) and IL-13 in lung cell supernatant from ovalbumin mice cells restimulated with antigen, and airway hyperresponsiveness to methacholine in ovalbumin mice. The main study findings were: (1) extracellular CypA and CypB levels were significantly increased in the airways of asthmatic mice; (2) CD147 was expressed by mouse eosinophils and CD4+ T cells and upregulated in activated CD4+ T cells; (3) CypA and CypB induced CD147-dependent chemotaxis of activated mouse CD4+ T cells but not eosinophils; (4) in vivo anti-CD147 monoclonal antibody (mAb) treatment resulted in a significant (up to 50%) decrease in the numbers of eosinophils and CD4+ T cells in lung tissues of ovalbumin mice, as well as a reduction in antigen-specific T-helper 2 (Th2) cytokine (IL-5 and IL-13) secretion; and (5) anti-CD147 mAb treatment reduced airway epithelial mucin production and bronchial hyperreactivity.

CONCLUSIONS. This study suggests that extracellular cyclophilins, through interaction with CD147, play a role in asthma-mediated lung inflammation and that anti-CD147 intervention significantly reduces several parameters of this inflammation.

REVIEWER COMMENTS. The pathogenesis of allergic asthma involves the recruitment of eosinophils and Th2 lymphocytes to airways and lung tissues, with resultant elaboration of cytotoxic proteins, mediators, and cytokines that induce disease pathology, such as increased mucus and bronchial hyperreactivity. Much attention has focused on chemokines that attract these inflammatory cells through interaction with chemokine receptors on leukocytes. The important chemokine-like activity of extracellular cyclophilins, via their interaction with CD147, was investigated in this study, and anti-CD147 treatment was found to significantly reduce leukocyte recruitment to inflamed lung tissues. Given the pathogenesis of allergic asthma, the targeting of cyclophilin–CD147 interaction using anti-CD147 mAb represents a potentially novel asthma therapy.

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