Cadherin-11 regulates fibroblast inflammation

Abstract

Fibroblasts are important participants in inflammation. Although not leukocytes, their capacity to produce cytokines, chemokines, and other inflammatory factors locally in tissues suggests that they can contribute to inflammatory diseases. For example, fibroblasts in a rheumatoid arthritis (RA) joint are a dominant source of IL-6 and RANKL in the synovium, both of which are therapeutic targets for inflammation and bone erosion. Previously, we found that fibroblasts can be targeted by mAb directed against cadherin-11 (cad-11), a mesenchymal cadherin that fibroblasts selectively express. Targeting cad-11 significantly reduced inflammation as assessed by joint swelling and clinical inflammation scores. However, the mechanism by which anti–cad-11 reduced inflammation was not known. Here, we show that cad-11 engagement induces synovial fibroblasts to secret proinflammatory cytokines including IL-6. Cad-11 engagement strongly synergized with TNF-α and IL-1β in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-κB for IL-6 induction. IL-6 levels in ankles of inflamed joints were reduced in cad-11 mutant mice compared to wild-type mice with inflammatory arthritis. Thus, we suggest that cad-11 modulates synovial fibroblasts to evoke inflammatory factors that may contribute to the inflammatory process in RA.

Estradiol Promotes M1-like Macrophage Activation through Cadherin-11 To Aggravate Temporomandibular Joint Inflammation in Rats

“…This mechanism may be related to the fact that cadherin-11 can stimulate the activation of Erk and NF-kB p65 in NR8383 macrophages. This hypothesis is consistent with a previous study that cadherin-11 directly induced cytokines, as well as activated MAPKs and the NF-kB pathway in synovial fibroblasts (40). NF-kB is a key regulator of proinflammatory cytokines, such as TNF-a and iNOS (41); both of them contribute to M1 macrophage polarization (15).…”

“…In addition, our previous study showed that E2 potentiates proinflammatory cytokines, including TNF-a and iNOS, via NF-kB activation in the synovial membrane (11). This phenomenon may also be related to the reasons why cadherin-11 is abundantly expressed in synoviocytes and is required for synoviocytes to produce the extracellular matrix, which modulates recruitment, activation, and retention of immune cells (40). Nevertheless, further study is required to elucidate the details of the contribution of cadherin-11 to M1-like macrophage activation in inflamed joints.…”

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

“…Prolonged inflammatory responses further compound the problem by initiating and propagating ECM remodeling. Both integrin-and OB-cadherin-mediated signaling have been implicated in inflammation, and strategies aimed at blocking the functions of these adhesion molecules have shown preliminary success in limiting inflammation-triggered maladaptive remodeling (Chang et al, 2011;Krieglstein et al, 2002;Lee et al, 2007;Schneider et al, 2012). The overlapping and integrated networks of chemical and mechanical signals that regulate the progression of fibrotic heart disease will continue to challenge the development of promising therapies.…”

“…It is also expressed in CFs, but the functional significance of this expression in the context of cardiac fibrosis and wound healing has not been studied. Given the known roles of OB-cadherin in inflammation and fibrosis in joint connective tissue and lungs, OB-cadherin is likely to have an important role in myocardial remodeling (Chang et al, 2011;Schneider et al, 2012 Fig. 3.…”

Down regulation of COX-2, IL-1β, TNF-α in cynoviocyte by essential oil of Fraxinus excelsior

“…In the healthy synovium, the FLS express Cadherin-11 (Cad-11) as the only cell type, whereas MLS express CD14 and CD68 [33,34] . First one is the detection of CD14 expression as a marker for macrophage [35], and second one the expression of CD14 with the reverse transcription polymerase chain reaction (RT-PCR). Total RNA extraction was performed using a commercial kit (SinaClon kit IRAN).…”