CCL17 drives the expression of MMP9 and MMP13 expression via ERK1/2 and NF-κB signaling pathways in rheumatoid arthritis.

Chemokine (CC motif) ligand 17 (CCL17), an inflammatory chemokine, has been shown to mediate pain and inflammation in animal models of arthritis. However, the specific molecular mechanisms by which CCL17 mediates its inflammatory functions remain largely unknown. Matrix metalloproteinases (MMPs), particularly MMP9 and MMP13, are cartilage degrading enzymes that are known to contribute to joint pain and inflammation in arthritis. These MMPs, produced in significant quantities by macrophages, facilitate the breakdown of the extracellular matrix and are regulated by various signaling pathways, including extracellular signal-related kinase (ERK1/2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, how CCL17 regulates downstream mediators in arthritis has not yet been elucidated. This study investigates the regulatory role of CCL17 on MMP expression in peripheral blood mononuclear cells (PBMCs) and plasma from rheumatoid arthritis (RA) patients, as well as in monocyte-derived macrophages (MDMs) from healthy donors. Analysis of RA patient samples revealed a positive correlation between CCL17 levels and MMP9/MMP13 expression. Furthermore, CCL17 treatment of MDMs resulted in an upregulation of MMP9 and MMP13 expression, correlating with increased activity of ERK1/2 and NF-κB. Markedly, pre-treatment with pharmacological inhibitors, U0126 (an ERK1/2 inhibitor) and NF-κB Activation Inhibitor IV (NF-κB inhibitor), in both MDMs and RA PBMCs, demonstrated that CCL17-driven MMP9 and MMP13 expression was critically dependent on ERK1/2 and NF-κB activation. Our findings provide new insights into possible mechanisms driving joint destruction in RA, highlighting potential benefits of targeting CCL17 and/or its downstream mediators as potential therapeutic strategies for treating inflammation.