Blocking Cyclophilins in the Chronic Phase of Asthma Reduces the Persistence of Leukocytes and Disease Reactivation

Abstract

Allergic asthma is characterized by acute influxes of proinflammatory leukocytes in response to allergen stimulation, followed by quiescent (chronic) periods between allergen challenges, during which sustained, low-level inflammation is evident. These chronic phases of disease are thought to be mediated by populations of leukocytes persisting within airways and tissues. The lack of any in situ proliferation by these cells, along with their limited lifespan, suggests that a continual recruitment of leukocytes from the circulation is needed to maintain disease chronicity. The mechanisms regulating this persistent recruitment of leukocytes are unknown. Although classic leukocyte-attracting chemokines are highly elevated after acute allergen challenge, they return to baseline levels within 24 hours, and remain close to undetectable during the chronic phase. In the present study, we investigated whether an alternative family of chemoattractants, namely, extracellular cyclophilins, might instead play a role in regulating the recruitment and persistence of leukocytes during chronic asthma, because their production is known to be more sustained during inflammatory responses. Using a new murine model of chronic allergic asthma, elevated concentrations of extracellular cyclophilin A, but not classic chemokines, were indeed detected during the chronic phase of asthma. Furthermore, 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. These findings suggest that blocking the function of cyclophilins during the chronic phase of asthma may provide a novel therapeutic strategy for regulating disease chronicity and severity.

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

“…CD147 is a type I transmembrane glycoprotein, a member of the immunoglobulin super-family, that is expressed by a wide array of cell types, including epithelial, endothelial and hematopoietic cells (6). CD147 is a signaling receptor for extracellular cyclophilins (Cyp) A and B (7,8), and recent publications have identified the CD147 signaling pathway induced by extracellular cyclophilins as a triggering mechanism regulating MMP expression and inflammation in atherosclerosis, rheumatoid arthritis, allergic and chronic lung disease (9)(10)(11)(12)(13)(14). Thus, we hypothesized that CD147 activation by extracellular cyclophilin may play a role in experimental BA as well.…”

The Expression of Cyclophilin A in Ovarian Endometrioma: Its Correlation with Recurrence and Vascularity

“…For example, Satoh et al (2013) reported that CyPA expression is significantly higher in the atherosclerotic plaque of arterial walls in patients with atherosclerosis. Additionally, Stemmy et al (2011) revealed a higher concentrations of extracellular CyPA in the chronic phase of asthma using a murine model. Billich et al (1997) found that CyPA levels were increased in the synovial fluids of patients with rheumatoid arthritis (RA).…”

“…Many of previous studies have clearly indicated that an overexpression of CyPA is correlated with poor outcomes in patients with inflammatory diseases (Stemmy et al 2011). During the inflammation process, CyPA exacerbates oxidative stress and inflammation .…”

“…Many of the previous reports have shown that the expression and/or circulating levels of CyPA are higher in the presence of disorders related to inflammatory conditions (Billich et al 1997;Yang et al 2007;Li et al 2008;Nigro et al 2011;Stemmy et al 2011;Satoh et al 2013;Ramachandran et al 2014). For example, Satoh et al (2013) reported that CyPA expression is significantly higher in the atherosclerotic plaque of arterial walls in patients with atherosclerosis.…”

“…It is known as an inflammatory mediator that is secreted from various types of cells in response to inflammatory stimuli such as hypoxia, oxidative stres, and infection. Previous reports have shown that the expression and/or circulating levels of CyPA are higher in the presence of several disorders such as diabetes mellitus, asthma, rheumatoid arthritis, cardiovascular disease, and cancer, which causes inflammatory conditions in the body (Billich et al 1997;Yang et al 2007;Li et al 2008;Nigro et al 2011;Stemmy et al 2011;Satoh et al 2013;Ramachandran et al 2014). During the inflammation process, the increased secretion of CyPA stimulates the production of cytokines as well as the migration of inflammatory cells, including monocytes/macrophages and neutrophils (Yang et al 2008;Tian-tian et al 2013).…”