Roles of tumour necrosis factor‐related weak inducer of apoptosis/fibroblast growth factor‐inducible 14 pathway in lupus nephritis

Abstract

KEY WORDS:fibroblast growth factor-inducible 14, glomerular basement membrane, lupus nephritis, proinflammatory cytokines, tumour necrosis factor-related weak inducer of apoptosis. Correspondence SUMMARY AT A GLANCEThis review describes evidence supporting a pathogenic role for tumour necrosis factorrelated weak inducer of apoptosis (TWEAK) in human and experimental lupus nephritis. Current understanding of TWEAK is integrated with known mechanisms of renal inflammation and fibrosis. This is highly relevant given early stage clinical studies with anti-TWEAK monoclonal antibodies. ABSTRACT:As one of the manifestations of patients with systemic lupus erythematosus, lupus nephritis (LN) has high morbidity and mortality. Although the explicit mechanism of LN remains to be fully elucidated, there is increasing evidence to support the notion that tumour necrosis factor-related weak inducer of apoptosis (TWEAK), acting via its sole receptor, fibroblast growth factorinducible 14 (Fn14), plays a pivotal role in such pathologic process. TWEAK/Fn14 interactions occur prominently in kidneys of LN, inducing inflammatory responses, angiogenesis, mesangial proliferation, filtration barrier injuries, renal fibrosis, etc. This review will specify the important roles of TWEAK/Fn14 pathway in the pathogenesis of LN with experimental data from cellular and animal models. Additionally, the raised levels of urinary and serum soluble TWEAK correlate with renal disease activity in patients with LN. The neutralizing antibodies targeting TWEAK or other approaches inhibiting TWEAK/Fn14 signals can attenuate renal damage in the murine lupus models. Therefore, to focus on TWEAK/Fn14 signalling may be promising in both clinical evaluation and the treatment of patients with LN.

TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus

“…TWEAK engages its sole receptor fibroblast growth factor-inducible 14 (Fn14) and modulates various cell types under inflammatory condition (10–12). TWEAK/Fn14 interaction plays an important role in the pathogenesis of tissue injuries in systemic lupus erythematosus, including lupus nephritis (13), neuropsychiatric disease (14), and cardiovascular disease (15). Besides, the TWEAK/Fn14 pathway is activated in skin lesions of MRL/lpr lupus-prone mice (16), and Fn14 deficiency protects these mice from CLE inflammation induced by UVB irradiation (17).…”

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

“…Although LN is classified into Class I to Class VI according to pathological patterns (2), renal fibrosis is definitely the common final outcome at the end stage (1). The fibrotic lesions are associated strongly with poor outcome of patients with LN (3). During the progression of renal fibrosis, profibrotic cytokines are continuously released, and consequently enhance the phenotype changes of resident cells as well as the accumulation of extracellular matrix (3, 4).…”

“…The fibrotic lesions are associated strongly with poor outcome of patients with LN (3). During the progression of renal fibrosis, profibrotic cytokines are continuously released, and consequently enhance the phenotype changes of resident cells as well as the accumulation of extracellular matrix (3, 4). Therefore, elucidation of the pathogenesis of renal fibrosis, especially the regulation of profibrotic cytokines, is important in the development of therapeutic strategies for patients with LN.…”

Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling

“…TWEAK is a significant proinflammatory cytokine in vitro and in vivo [20]. TWEAK/Fn14 interaction has been shown to mediate diverse bioactivities involving the activation of cell proliferation, migration, or apoptosis; the induction of vasculitis and angiogenesis; the production of inflammatory cytokines; and the promotion of fibrogenic responses [15, 20]. In in vitro experiments, TWEAK has been found to induce the production of multiple cytokines, including regulated on activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), interferon-γ–induced protein 10 (IP-10), macrophage inflammatory protein-1 alpha (MIP-1α), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) [14, 21].…”

“…In recent years, increasing evidence has indicated that the TWEAK/Fn14 signaling pathway plays a pivotal role in the pathogenesis of lupus erythematosus, which presents cutaneous, renal, and neuropsychiatric diseases [15-17]. Moreover, the TWEAK/Fn14 signals participate in the development of various dermatoses, such as psoriasis [7], atopic dermatitis [8], cutaneous vasculitis [18], human papillomavirus (HPV) infection [9], and bullous pemphigoid [10].…”