Background: Circulating fibrocytes, trafficking into bronchial sub-epithelial zone, actively participate in airway remodeling of patients with severe or treatment refractory asthma. IL-4 and IL-13 participate in the pathogenesis of asthma, including reduction in apical junction, and induction of epithelial permeability, goblet cell hyperplasia.

Objectives: Production of T2 cytokines by infiltrating fibrocytes underneath airway epithelium may be involved in airway remodeling in T2-high asthma.

Methods and Results: We investigated circulating fibrocytes expressing IL-4, IL-5 or IL-13 (T2 fibrocytes) in the peripheral blood of 14 stable (ACT>24) allergic asthmatics (CAA) and 16 uncontrolled (ACT <19) allergic asthmatics (UAA). Patients with UAA had higher number of circulating fibrocytes, and higher proportion of T2 fibrocytes in circulating fibrocytes than CAA. The immune-fluorescence and RT/PCR studies revealed increased expression of IL-4 and IL-13 in fibrocytes from UAA, compared to CAA patients. The bronchial tissue T2 fibrocytes also increased in UAA, compared with CAA. IL-4 and IL-13 produced by T2 fibrocytes of UAA, through IL-4R?, mediated fibrocyte ?-SMA⁺ transformation, CTGF synthesis and CCR7 expression, increased fibroblast proliferation and matrix proteins production, and induced ALI cultured epithelial cells MUC5AC⁺ metaplasia, decreasing junction protein expression, leading to an increased TEER and para-cellular flux of dextran.

Conclusion: Circulating T2 fibrocytes of asthmatics migrating to airway sub-epithelial areas contribute to airway remodeling by releasing IL-4 and IL-13 to induce epithelial disruption, mucus metaplasia and increase fibrogenesis.