TY - JOUR
T1 - Activation of Toll-like Receptor-2 by Endogenous Matrix Metalloproteinase-2 Modulates Dendritic-Cell-Mediated Inflammatory Responses
AU - Godefroy, Emmanuelle
AU - Gallois, Anne
AU - Idoyaga, Juliana
AU - Merad, Miriam
AU - Tung, Navpreet
AU - Monu, Ngozi
AU - Saenger, Yvonne
AU - Fu, Yichun
AU - Ravindran, Rajesh
AU - Pulendran, Bali
AU - Jotereau, Francine
AU - Trombetta, Sergio
AU - Bhardwaj, Nina
N1 - Funding Information:
We thank Elizabeth Miller-Saks, Olivier Manches, and Ines Da Silva (New York University) for critical reading of this manuscript. This work was supported by the Cancer Research Institute (CLIP award), the Ludwig Institute for Cancer Research, the Alliance for Lupus Research, the Melanoma Research Alliance, the Bill and Melinda Gates Foundation, the American Cancer Society, and the following NIH awards, R01 AI071078, CCSG 5 P30 CA16087 (N.B.). B.P. and R.R. were supported the following NIH grants: R37 AI048638, R37 DK057665, U19 AI057266, and U19 AI090023. J.I. was supported by NIH/NIAMS grant 5K99AR062595.
Publisher Copyright:
© 2014 The Authors.
PY - 2014/12/11
Y1 - 2014/12/11
N2 - 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 Tcells toward type 2 responses invivo, 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 etal. 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 invitro and invivo. This may represent a key immune regulatory mechanism involved in a variety of inflammatory disorders.
AB - 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 Tcells toward type 2 responses invivo, 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 etal. 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 invitro and invivo. This may represent a key immune regulatory mechanism involved in a variety of inflammatory disorders.
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U2 - 10.1016/j.celrep.2014.10.067
DO - 10.1016/j.celrep.2014.10.067
M3 - Article
C2 - 25466255
AN - SCOPUS:84915766493
SN - 2211-1247
VL - 9
SP - 1856
EP - 1870
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -