MMP induced by Gr-1+ cells are crucial for recruitment of Th cells into the airways

Abstract

Th2 lymphocytes deliver essential signals for induction of asthmatic airway inflammation. We previously found that airway antigen challenge induces recruitment of Gr-1(+) neutrophils prior to the recruitment of Th2 cells. We examined, therefore, whether Gr-1(+) cells contribute to the development of Th2-dependent airway inflammation. Systemic depletion of Gr-1(+) cells using the RB6-8C5 monoclonal antibody reduced Th2 cell recruitment following i.n. antigen challenge. The levels of both MMP-9 and the tissue inhibitor of matrix metalloproteinases-1 mRNA were up-regulated in the lungs of mice 12 h after i.n. antigen challenge. Up-regulation of tissue inhibitor of matrix metalloproteinases-1 was independent of Gr-1(+) cells, whereas up-regulation of MMP-9 RNA and total gelatinolytic activity was dramatically reduced in mice depleted of Gr-1(+) cells. At 24 h after challenge, total lung collagenolytic activity was also up-regulated, in a Gr-1(+) cell-dependent fashion. Systemic inhibition of MMP-8 and MMP-9 reduced the airway recruitment of Th cells, resulting in significantly reduced eosinophilic inflammation. These data suggest that antigen challenge via the airway activates Gr-1(+) cells and consequently MMP to facilitate the recruitment of Th cells in the airway inflammatory response.