Double-Stranded RNA Enhances Matrix Metalloproteinase-1 and -13 Expressions through TLR3-Dependent Activation of Transglutaminase 2 in Dermal Fibroblasts.

Ah-Young Hong,In-Gyu Kim,Ji-Woong Shin,Seok-Jin Lee,Eui Man Jeong,Ki Baek Lee

doi:10.3390/ijms23052709

Abstract

UV-irradiation induces the secretion of double-stranded RNA (dsRNA) derived from damaged noncoding RNAs in keratinocytes, which enhance the expression of matrix metalloproteinases (MMP) in non-irradiated dermal fibroblasts, leading to dysregulation of extracellular matrix homeostasis. However, the signaling pathway responsible for dsRNA-induced MMP expression has not been fully understood. Transglutaminase 2 (TG2) is an enzyme that modifies substrate proteins by incorporating polyamine or crosslinking of proteins, thereby regulating their functions. In this study, we showed that TG2 mediates dsRNA-induced MMP-1 expression through NF-κB activation. Treatment of poly(I:C), a synthetic dsRNA analogue binding to toll-like receptor 3 (TLR3), generates ROS, which in turn activates TG2 in dermal fibroblast. Subsequently, TG2 activity enhances translocation of p65 into the nucleus, where it augments transcription of MMP. We confirmed these results by assessing the level of MMP expression in Tlr3−/−, TG2-knockdowned and Tgm2−/− dermal fibroblasts after poly(I:C)-treatment. Moreover, treatment with quercetin showed dose-dependent suppression of poly(I:C)-induced MMP expression. Furthermore, ex vivo cultured skin from Tgm2−/− mice exhibited a significantly reduced level of MMP mRNA compared with those from wild-type mice. Our results indicate that TG2 is a critical regulator in dsRNA-induced MMP expression, providing a new target and molecular basis for antioxidant therapy in preventing collagen degradation.

Highlights

Skin wrinkling is a prominent feature of aged skin and thought to be caused by an increase of reactive oxygen species (ROS) production due to mitochondrial dysfunction of senescent dermal fibroblast [1]
To test whether Transglutaminase 2 (TG2) is involved in the regulation of Double stranded RNAs (dsRNA)-induced matrix metalloproteinases (MMP) expression, we examined the effect of TG2 knock-down on the levels of MMP expression
These results indicate that TG2 serves as an effector enzyme that links dsRNA and NF-κB activation in dermal fibroblasts, resulting in extracellular matrix (ECM) dysregulation by promoting MMPs’ expression

Summary

Introduction

Skin wrinkling is a prominent feature of aged skin and thought to be caused by an increase of reactive oxygen species (ROS) production due to mitochondrial dysfunction of senescent dermal fibroblast [1]. In sun-exposed skin, UV irradiation is known to induce ROS generation such as singlet oxygen (1O2), superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (OH·), and aggravates the dysregulation of ECM remodeling through MMP-1 expression, resulting in premature skin aging [3]. Double stranded RNAs (dsRNA) are generated in virus-infected cells during its replication, and play a role in eliciting anti-viral responses by binding toll-like receptor 3 (TLR3), a member of the pattern recognition receptor family, and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) [4]. Poly(I:C) induces MMPs’ expression in human dermal fibroblasts [7] These findings indicate that dsRNA functions as a signaling molecule to induce skin responses in response to genotoxic stresses in addition to viral infection

Methods

Results

Conclusion