The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases.
The TWEAK/Fn14 pathway is a ligand/receptor pair of the TNFSF that has emerged as a prominent player in normal and pathological tissue remodeling. TWEAK/Fn14 pathway activation drives many processes relevant to autoimmune and inflammatory diseases. IBDs, including CD and UC, are chronic, relapsing inflammatory diseases of the GI tract. These diseases differ in their clinical, macroscopic, and histopathological presentation; however, pathological processes that prominently contribute, more or less in each case, include breakdown of the mucosal epithelial barrier, chronic inflammation, and tissue remodeling with fibrosis. TWEAK may promote the pathogenesis of IBD by signaling through Fn14, which can be up-regulated on IECs, thereby contributing to breakdown of the mucosal barrier; the induction of IEC-derived mediators that promote chronic inflammation and shape gut immunity against commensal flora; and delayed healing and fibrosis. TWEAK may also exert its action on endothelial and stromal cell types, including smooth muscle cells and fibroblasts, to promote chronic inflammation, dysregulated tissue repair, and fibrosis. Here, we review the data supporting an emerging role of the TWEAK/Fn14 pathway in autoimmune and inflammatory diseases, with a particular focus on IBD, and discuss how it interplays with other prominent pathways, including IL-13, TNF-α, and TGF-β, to aggravate and perpetuate the pathological processes underlying IBD.
Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Taeko
T
Dohi
Linda C
LC
Burkly
D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000074049:Cytokine TWEAK; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000502:physiology*
D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors