This project will explore how distinct subsets of macrophages moderates inflammation and remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury. 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 immunosuppressive and ECM-degrading programs in 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 promotes 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 hypotheses that MMP10 sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on immuno-regulatory and ECM-remodeling programs in M2-biased macrophages.
The aims are to 1) determine the role of MMP10 in regulating macrophage activation and immunosuppressive function in lung fibrosis.; 2) identity the ECM-degrading proteinases controlled by MMP10; 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 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 new, effective strategies 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|