This new project will explore how distinct subsets of macrophages remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury, infection, or allergen challenge. The mechanistic focus will center on how stromelysin-2 (MMP10), a member of the matrix metalloproteinase family of extracellular endopeptidases, functions in a cell-autonomous manner to control the activation of ECM-degrading programs in alternatively activated macrophages. Key preliminary data demonstrate that MMP10 is induced in macrophages and functions to drive their activation status from pro-inflammatory cells (i.e., M1-biased) to immunosuppressive macrophages (i.e., M2-biased). M2 macrophages are considered to be remodeling competent, and additional preliminary data demonstrates that MMP10 drives the activation of an effective remodeling phenotype in M2 macrophages by regulating the expression of other metalloproteinases with matrix-degrading activity. This project will test the hypothesis that MMP10 is induced in response to specific stimuli in an injured/infected tissue environment and sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on ECM-remodeling programs in M2-biased macrophages.
The aims are to 1) determine the mechanisms controlling MMP10 expression in macrophages and role of MMP10 in models of lung disease; 2) identity the ECM-degrading proteinases expressed by M2 macrophages; and 3) identify and validate the MMP10 substrate affecting macrophage activation. The approach will include the use of genetically-defined mouse models, mouse and human cells, and various analytical approaches.
These studies will characterize a novel, fundamental mechanism controlling macrophage activation and tissue remodeling in lung disease. Knowledge from this work may provide an effective strategy to limit inflammation-associated damage not only in lung, but in all tissues.
| Rohani, Maryam G; Dimitrova, Elizabeth; Beppu, Andrew et al. (2018) Macrophage MMP10 Regulates TLR7-Mediated Tolerance. Front Immunol 9:2817 |
| Secor, Patrick R; Michaels, Lia A; Smigiel, Kate S et al. (2017) Filamentous Bacteriophage Produced by Pseudomonas aeruginosa Alters the Inflammatory Response and Promotes Noninvasive Infection In Vivo. Infect Immun 85: |
| Wight, Thomas N; Frevert, Charles W; Debley, Jason S et al. (2017) Interplay of extracellular matrix and leukocytes in lung inflammation. Cell Immunol 312:1-14 |
| McMahan, Ryan S; Birkland, Timothy P; Smigiel, Kate S et al. (2016) Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation. J Immunol 197:899-909 |
