Activation of Toll-like Receptor-2 by Endogenous Matrix Metalloproteinase-2 Modulates Dendritic-Cell-Mediated Inflammatory Responses
Emmanuelle Godefroy,
Anne Gallois,
Juliana Idoyaga,
Miriam Merad,
Navpreet Tung,
Ngozi Monu,
Yvonne Saenger,
Yichun Fu,
Rajesh Ravindran,
Bali Pulendran,
Francine Jotereau,
Sergio Trombetta,
Nina Bhardwaj
Affiliations
Emmanuelle Godefroy
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Anne Gallois
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Juliana Idoyaga
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA; Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
Miriam Merad
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Navpreet Tung
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Ngozi Monu
New York University Langone Medical Center, Cancer Institute, New York, NY 10016, USA
Yvonne Saenger
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Yichun Fu
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA
Rajesh Ravindran
Emory Vaccine Center, Department of Pathology, Emory University, Atlanta, GA 30322, USA
Bali Pulendran
Emory Vaccine Center, Department of Pathology, Emory University, Atlanta, GA 30322, USA
Francine Jotereau
INSERM U892, 44093 Nantes, France
Sergio Trombetta
New York University Langone Medical Center, Cancer Institute, New York, NY 10016, USA
Nina Bhardwaj
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY 10029, USA; Corresponding author
Summary: Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity. : Godefroy et al. now demonstrate that matrix metalloproteinase-2 (MMP-2) directly interacts with and activates dendritic cells (DCs) via Toll-like receptor-2. MMP-2-exposed DCs upregulate OX40L, promoting type 2 polarization both in vitro and in vivo. This may represent a key immune regulatory mechanism involved in a variety of inflammatory disorders.
