Scientists at the Icahn School of Medicine at Mount Sinai report that a key protein may represent a novel way to use the immune system to speed healing and counter inflammatory, infectious, and autoimmune diseases. The team published its study (“Activation of Toll-like Receptor-2 by Endogenous Matrix Metalloproteinase-2 Modulates Dendritic-Cell-Mediated Inflammatory Responses”) in Cell Reports.
The current research results revolve around proteinases. Matrix metalloproteinases (MMPs) specifically target the extracellular matrix, the noncell, structural framework within tissues. Beyond that role, the new study found that one member of this family, MMP-2, has another signaling role related to the human immune system. It may shift a set of cells to become part of immune response that accelerates healing in some cases, but may worsen inflammatory disease in others.
“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,” wrote the investigators. “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.”
Drug designers may be able to leverage the newfound MM-2 mechanisms to prevent the contribution of inflammatory signals to tumor growth and autoimmune diseases, or to promote wound healing.
“Our results show that MMP-2 uses a multitude of mechanisms to modulate the immune system,” says the study's lead investigator Nina Bhardwaj, M.D., Ph.D., director of immunotherapy, Tisch Cancer Center at Mount Sinai, professor of Medicine, Hematology and Oncology, Icahn School of Medicine. “These data provides context to how this mechanism happens and could lead to novel treatments.”
If MMP-2 signaling leads to the presence of more Th2 T cells, it means Th2 cells will secrete more inflammatory TH2 cytokines like TNF-alpha, and interleukins 4 and 13, which fight parasite infections, but that can also contribute to autoimmune diseases if present in too large amounts. MMP-2 is also over-expressed in tumors, where it promotes cancer progression. This may in part be due to its ability to skew T cells toward Th2 differentiation, a process called type-2 polarization.
Th2 cells also contribute to wound healing because they produce cytokines, which fight infection and ultimately repair tissue. The tissue repair functions of MMP-2's may be due to the ability to drive Th2 immune response.
“MMP-2-mediated signaling either through direct injection or through mimics could promote wound healing but these proposed functions will require further investigation in disease-specific models,” says Dr. Bhardwaj. “Further discovery of new MMP-2 functions could lead to new reagents of inflammatory responses.”