The role of extracellular cyclophilins in chronic allergic asthma
Open AccessAllergic asthma is characterized by acute influxes of pro-inflammatory leukocytes in response to allergen stimulation, followed by quiescent (chronic) periods between allergen challenges in which sustained low-level inflammation is observed. These chronic phases of disease are thought to be mediated by populations of leukocytes persisting within airways and lung tissues. The mechanisms regulating these persistent leukocyte populations are unknown. While classical leukocyte-attracting chemokines are highly elevated following acute allergen challenge, in both humans and animal models they return to baseline levels within 24 h and remain close to undetectable during the chronic phase. In the current studies we investigated whether an alternative family of chemoattractants, extracellular cyclophilins, might instead play a role in regulating leukocyte recruitment and persistence during chronic asthma. We optimized and characterized a new mouse model of chronic allergic asthma, and show elevated levels of extracellular cyclophilin A, but not classical chemokines, throughout the chronic phase of asthma. Further, blocking the activity of cyclophilins during this phase reduced the number of persisting leukocytes by up to 80%. This reduction was also associated with a significant inhibition of acute disease reactivation upon subsequent allergen challenge: leukocyte infiltration was reduced by more than 60%, and this translated to profound improvements in lung function. We also investigated whether cyclophilins were present in nasal wash samples of human asthma patients in the chronic phase of disease. We observed significant increases in cyclophilin B in the asthma cohort, as well as significant associations between cyclophilins and several parameters of asthma severity.
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