Rhinovirus (RV), which is associated with acute exacerbations, also causes persistent lung inflammation in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not well-known. Recently, we demonstrated that RV causes persistent lung inflammation with accumulation of a subset of macrophages (CD11b(+)/CD11c(+)), and CD8(+) T cells, and progression of emphysema. In the present study, we examined the mechanisms underlying the RV-induced persistent inflammation and progression of emphysema in mice with COPD phenotype. Our results demonstrate that at 14 days post-RV infection, in addition to sustained increase in CCL3, CXCL-10 and IFN-gamma expression as previously observed, levels of interleukin-33 (IL-33), a ligand for ST2 receptor, and matrix metalloproteinase (MMP)12 are also elevated in mice with COPD phenotype, but not in normal mice. Further, MMP12 was primarily expressed in CD11b(+)/CD11c(+) macrophages. Neutralization of ST2, reduced the expression of CXCL-10 and IFN-gamma and attenuated accumulation of CD11b(+)/CD11c(+) macrophages, neutrophils and CD8(+) T cells in COPD mice. Neutralization of IFN-gamma, or ST2 attenuated MMP12 expression and prevented progression of emphysema in these mice. Taken together, our results indicate that RV may stimulate expression of CXCL-10 and IFN-gamma via activation of ST2/IL-33 signaling axis, which in turn promote accumulation of CD11b+/CD11c+ macrophages and CD8(+) T cells. Furthermore, RV-induced IFN-gamma stimulates MMP12 expression particularly in CD11b(+)/CD11c(+) macrophages, which may degrade alveolar walls thus leading to progression of emphysema in these mice. In conclusion, our data suggest an important role for ST2/IL-33 signaling axis in RV-induced pathological changes in COPD mice.