Activation of Toll-like Receptor-2 by Endogenous Matrix Metalloproteinase-2 Modulates Dendritic-Cell-Mediated Inflammatory Responses

Abstract

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 up-regulate 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 up-regulation on DCs and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells towards type-2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type-2 polarization may represent a key immune regulatory mechanism to protect against a broad array of disorders, such as inflammatory, infectious and autoimmune diseases, which can be hijacked by tumors to evade immunity.

MMP2 and MMP9 are Associated with Apical Periodontitis Progression and Might be Modulated by TLR2 and MyD88

“…MMP2 modulates many physiological conditions including wound repair and tissue remodeling (22). In physiological condition, MMP2 is expressed by periodontal ligament cells (23) and acts in response to infection, tissue remodeling and injury.…”

Modulation of innate immunity in the tumor microenvironment

“…Analysis of serum cytokines revealed a distinct inflammatory signature (TNF-α and IL-6) only in sera obtained from WT mice where as the sera from knockout mice had no inflammatory cytokines. Similarly, WT and tlr2 − / − mice adoptively transferred with OT-II cells and injected with OVA + MMP-2 revealed T H 2 polarization upon re-stimulation only in WT-derived T cells and not in tlr2 − / − cells [15]. Taken together, these studies indicate that MMP-2 primes DCs to skew the adaptive immune response toward a pro-tumorigenic T H 2 phenotype through multiple mechanisms.…”

“…Furthermore, OX40L-mediated T H 2 differentiation was reversed by introduction of exogenous IL-12, indicating that the mechanism of DC-mediated T cell differentiation is amenable to manipulation by pharmacological intervention [12–14]. We found that apart from directly inhibiting IL-12 and consequent T H 1 polarization, exogenous MMP-2 also enhanced T H 2-polarization by upregulating OX40L expression on DCs [11, 15]. It is interesting to note that while only active MMP-2 could degrade IFNAR1 and thus inhibit IL-12 secretion, both active and inactive forms of MMP-2 were able to enhance OX40L expression and stimulate secretion of inflammatory cytokines via the canonical NFκB pathway.…”

“…It is interesting to note that while only active MMP-2 could degrade IFNAR1 and thus inhibit IL-12 secretion, both active and inactive forms of MMP-2 were able to enhance OX40L expression and stimulate secretion of inflammatory cytokines via the canonical NFκB pathway. Screening for MMP-2-signaling partners led us to identify Toll-like receptor-2 (TLR-2) as a direct binding partner for MMP-2, independently of TLR-1 and TLR-6 [15]. These findings were corroborated in human monocyte-derived DCs, murine bone marrow-derived DCs as well as in HEK cells over expressing TLR-2.…”

Advances in cancer immunology and cancer immunotherapeutics

“…Recently, matrix metalloproteinase-2 (MMP-2) produced by the tumor cells has been linked to promoting TH2 response by acting directly as an antigen, increased OX40L expression and DCs receptor alteration. [55] Tumor cells also develop perforin and granzyme inhibitors to resist CD8+ T-cell and NK cell-induced cytotoxicity. [56] Various other molecules are also involved (discussed elsewhere in this article) which may ultimately lead to immune evasion by tumor cells.…”