Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation
Sarah J McMillan1, Jennifer Kearley, J Darren Campbell
1Division of Biomedical Sciences, Faculty of Medicine Imperial College, London, United Kingdom.
Abstract:
Matrix metalloproteinases (MMPs) are a large family of endopeptidases that proteolytically degrade extracellular matrix. Many different cells produce MMP-9, and levels have been shown to be up-regulated in patients with allergic asthma. The aim of this study was to investigate the in vivo role of MMP-9 during allergen-induced airway inflammation. Acute allergic pulmonary eosinophilia was established in MMP-9 knockout (KO) and wild-type (WT) control mice by sensitization and challenge with OVA. Cell recruitment was significantly increased in both bronchoalveolar lavage (BAL) and lung tissue compartments in MMP-9 KO mice compared with WT mice. This heightened cell recruitment was primarily due to increased eosinophils and Th2 cells in the BAL and lung tissue of MMP-9 KO mice in comparison with WT controls. Moreover, levels of the Th2 cytokines, IL-4 and IL-13, and the chemokines eotaxin/CCL11 and macrophage-derived chemokine/CCL22 were substantially increased in MMP-9 KO mice compared with WT after OVA challenge. Resolution of eosinophilia was similar between MMP-9 KO and WT mice, but Th2 cells persisted in BAL and lungs of MMP-9 KO mice for longer than in WT mice. Our results indicate that MMP-9 is critically involved in the recruitment of eosinophils and Th2 cells to the lung following allergen challenge, and suggest that MMP-9 plays a role in the development of Th2 responses to allergen.
Insights
Matrix metalloproteinase-9 (MMP-9) deficiency exacerbates allergic airway inflammation by increasing eosinophil and Th2 cell recruitment. MMP-9 plays a critical role in managing these cellular responses in asthma models.
Area of Science:
- Immunology
- Respiratory Medicine
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are enzymes degrading the extracellular matrix.
- MMP-9 is implicated in various inflammatory conditions, with elevated levels observed in allergic asthma.
- Understanding MMP-9's role in airway inflammation is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the in vivo function of MMP-9 in allergen-induced airway inflammation.
- To elucidate the specific mechanisms by which MMP-9 influences cellular recruitment and cytokine profiles in asthma.
Main Methods:
- Utilized a murine model of acute allergic pulmonary eosinophilia induced by ovalbumin (OVA) sensitization and challenge.
- Compared cellular recruitment, cytokine levels, and chemokine expression in MMP-9 knockout (KO) mice versus wild-type (WT) controls.
- Assessed the resolution of inflammation and persistence of specific immune cells.
Main Results:
- MMP-9 KO mice exhibited significantly increased recruitment of eosinophils and Th2 cells to the lungs and bronchoalveolar lavage (BAL) fluid compared to WT mice.
- Elevated levels of Th2 cytokines (IL-4, IL-13) and chemokines (eotaxin/CCL11, macrophage-derived chemokine/CCL22) were observed in MMP-9 KO mice.
- While eosinophil resolution was similar, Th2 cells persisted longer in MMP-9 KO mice.
Conclusions:
- MMP-9 is critically involved in regulating the lung's inflammatory response to allergens.
- MMP-9 plays a significant role in controlling the recruitment of eosinophils and Th2 cells during allergic airway inflammation.
- Targeting MMP-9 may offer a therapeutic strategy for modulating Th2-driven allergic responses in asthma.
