Extracellular Vimentin signaling in periodontitis and rheumatoid arthritis with special focus on leucine-rich repeat containing 15 binding.

Inflammatory diseases of connective tissues such as periodontitis and rheumatoid arthritis exhibit localized destruction of matrix collagen and loss of tissue function. These diseases are driven by interconnected signaling pathways that determine disease progression and severity. Both periodontitis and rheumatoid arthritis involve the release of extracellular Vimentin (ECV) from stromal and immune cells at diseased sites, but the processes by which ECV binds to cells and promotes inflammatory signaling are not well defined. Recent data point to several putative ECV receptor proteins, one of which is Leucine-Rich Repeat Containing 15, an orphan receptor and cancer-associated fibroblast marker that contributes to inflammation and matrix destruction. Here, we consider the roles of ECV and LRRC15 in connective tissue diseases and discuss how their interactions may promote matrix destruction. We propose that ECV and LRRC15 signal through β1-integrin/FAK, Wnt/β-catenin, and NF-κB to promote cell adhesion, migration and matrix degradation by local fibroblast and immune cell populations. To obtain further insights into ECV-LRRC15 engagement, we used in silico modelling to predict the most likely binding conformation of the ECV-LRRC15 interaction with MEGADOCK. The most probable model suggests that the convex face of the LRRC15 leucine-rich repeat loop binds to two sites on the α-helices of Vimentin rod domains and to one site on Vimentin's N-terminal head domain, potentially signaling through this interface. In this review, we provide an in-depth overview of the functional links between ECV and LRRC15 and discuss their potential roles as drivers of matrix destruction in periodontitis and rheumatoid arthritis.