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A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.

ABSTRACT: Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting that they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the present study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA to specifically target extracellular pools of cyclophilins. In this study, we show that treatment with this compound in a mouse model of allergic lung inflammation demonstrates up to 80% reduction in inflammation, directly inhibits the recruitment of Ag-specific CD4(+) T cells, and works equally well when delivered at 100-fold lower doses directly to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular functions of cyclophilins may provide an approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, Ag-specific CD4(+) T cells, into inflamed airways and lungs.

SUBMITTER: Balsley MA

PROVIDER: S-EPMC3603141 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.

Balsley Molly A MA Malesevic Miroslav M Stemmy Erik J EJ Gigley Jason J Jurjus Rosalyn A RA Herzog Dallen D Bukrinsky Michael I MI Fischer Gunter G Constant Stephanie L SL

Journal of immunology (Baltimore, Md. : 1950) 20101105 12

Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic propertie ...[more]

PMID: 21057089

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Project description:The IL-4 receptor ? (IL-4R?) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4R? expression on both bone marrow-derived and non-bone marrow-derived cells contributed to the severity of allergic lung inflammation. There was a correlation between the number of macrophages expressing the IL-4R?, CD11b, and IA(d), and the degree of eosinophilia in ovalbumin challenged mice. The engagement of the IL-4R? by IL-4 or IL-13 is able to stimulate the alternative activation of macrophages (AAM). The presence of AAM has been correlated with inflammatory responses to parasites and allergens. Therefore, we hypothesized that IL-4R?? AAM play an active role in allergic lung inflammation. To directly determine the role of AAM in allergic lung inflammation, M-CSF-dependent macrophages (BMM) were prepared from the bone-marrow of IL-4R? positive and negative mice and transferred to IL-4R?xRAG2(-/-) mice. Wild type TH2 cells were provided exogenously.Mice receiving IL-4R?(+/+) BMM showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4R?(-/-) BMM. As expected, the eosinophilic inflammation was dependent on the presence of TH2 cells. Furthermore, we observed an increase in cells expressing F4/80 and Mac3, and the AAM marker YM1/2 in the lungs of mice receiving IL-4R?(+/+) BMM. The BAL fluid from these mice contained elevated levels of eotaxin-1, RANTES, and CCL2.These results demonstrate that transfer of IL-4R? + macrophages is sufficient to enhance TH2-driven, allergic inflammation. They further show that stimulation of macrophages through IL-4R? leads to their alternative activation and positive contribution to the TH2-driven allergic inflammatory response in the lung. Since an increase in AAM and their products has been observed in patients with asthma exacerbations, these results suggest that AAM may be targeted to alleviate exacerbations.

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Dataset Information

A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.

Publications

A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.

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