During events ranging from host defense to chronic inflammatory disease states, macrophages (MOs) infiltrate affected interstitial tissues where they can participate in both the proteolytic remodeling of the extracellular matrix and local immune responses. MOs have long been assumed to mobilize proteolytic enzymes (particularly those belonging to the matrix metalloproteinase gene family) in order to remodel the extracellular matrix. However, increasing evidence suggests that MMPs can also regulate cell function independently of their matrix remodeling activities. In an attempt to characterize matrix metalloproteinase-dependent versus -independent functions in MOs, we have recently focused our attention on the membrane-anchored protease, MT1-MMP - the single MMP family member whose deletion in mice results in a profound increase in morbidity and mortality. In recently reported studies designed to compare and contrast the function of wild-type and MT1- MMP-null MOs, we discovered that MO-derived MT1-MMP acts as a previously unsuspected transactivator of the gene networks central to MO inflammatory responses. MT1-MMP exerts these effects on MO function by controlling a novel regulatory axis wherein LPS-TLR4 interactions trigger MT1-MMP expression which then acts as a required activator of PI3K?/Akt/GSK3 signaling and the Mi-2/NuRD complex of nucleosome remodeling factors. Importantly, but unexpectedly, MT1-MMP exerts control over MO immune responses by trafficking into the nuclear compartment where it associates with the PI3K? promoter. While similar - if not identical - processes are operative in human cells, the mechanisms that control MT1-MMP nuclear trafficking and translocation remain undefined as do the processes that control MT1-MMP-DNA binding interactions or target gene selection. Furthermore, independent of MT1-MMP function in the nuclear compartment, the proteinase also serves as a key effector of MO-mediated turnover of the extracellular matrix, particularly those components associated with basement membranes, the specialized connective tissue barriers that underlies all epithelial and endothelial cells. As such, we propose to i) characterize the regulatory mechanisms underlying MT1-MMP nuclear trafficking and nucleoplasm translocation, ii) identify the DNA-binding partners that mediate MT1-MMP-mediated nuclear transcriptional activation iii) define the role of MT1-MMP as the dominant mediator of extracellular matrix remodeling and iv) characterize the role of MO MT1-MMP in regulating immune responses in vivo. These studies should provide novel insights into newly identified, MO- dependent nucleosomal remodeling pathways that mark chronic inflammatory events central to host defense as well as inflammatory disease states. As MT-MMPs and PI3K? are expressed in almost all immune cell populations, these results should serve to outline a new paradigm in inflammation and identification of control mechanisms that may prove conducive to therapeutic intervention.

Public Health Relevance

Macrophages play a key role in the tissue remodeling events and regulation of immune responses associated with host defense and inflammation. Currently, the molecular mechanisms that orchestrate macrophage-mediated proteolytic events with immune responses are unknown. Herein, we outline a series of new animal models and experimental approaches utilizing mouse as well as human myeloid cells that have identified a novel pathway wherein the membrane-anchored matrix metalloproteinase, MT1-MMP, regulates the transcriptional programs that underlie macrophage-dependent immune responses and tissue-degradative proteolytic activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI105068-01A1
Application #
8630187
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$349,875
Indirect Cost
$124,875
Name
University of Michigan Ann Arbor
Department
None
Type
Organized Research Units
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109