TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease.
ABSTRACT First described as a weak apoptosis inducer, the TNF superfamily ligand TWEAK has since emerged as a cytokine that regulates multiple cellular responses, including proinflammatory activity, angiogenesis and cell proliferation, suggesting roles in inflammation and cancer. More recently TWEAK's ability to regulate progenitor cell fate was elucidated. Experiments using genetic overexpression and pathway inhibition or deficiency in mice indicate that TWEAK coordinates inflammatory and progenitor cell responses in settings of acute injury through its highly inducible receptor, FGF-inducible molecule 14 (Fn14), establishing the pathway's physiological role in facilitating acute tissue repair. In contrast, in chronic inflammatory disease models characterized by persistent TWEAK/Fn14 activation, TWEAK functions as a novel pathogenic mediator by amplifying inflammation, promoting tissue damage and potentially impeding endogenous repair mechanisms. Herein we aim not only to review the multifaceted functions of this emerging pathway, but also propose a conceptual framework for TWEAK/Fn14 pathway function in health and disease, supported by studies employing TWEAK and Fn14 deficient mice and anti-TWEAK blocking mAbs in acute injury and inflammatory disease settings. In addition to a perspective of the biology, we discuss potential therapeutic strategies targeting this pathway for the treatment of tissue injury, chronic inflammatory diseases and cancer.
- SourceAvailable from: Saulo Gantes Tractenberg[Show abstract] [Hide abstract]
ABSTRACT: Background Both early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine. Methods This study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment. Results The CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF-alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity. Conclusions This is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels.Journal of Psychiatric Research 06/2014; DOI:10.1016/j.jpsychires.2014.02.017 · 4.09 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Coral reefs provide habitats for a disproportionate number of marine species relative to the small area of the oceans that they occupy. The mutualism between the cnidarian animal hosts and their intracellular dinoflagellate symbionts provides the nutritional foundation for coral growth and formation of reef structures, as algal photosynthesis can provide >90% of the host's total energy. Disruption of this symbiosis ("coral bleaching") is occurring on a large scale due primarily to anthropogenic factors and poses a major threat to the future of coral reefs. Despite the importance of this symbiosis, the cellular mechanisms involved in its establishment, maintenance, and breakdown remain largely unknown. Here we report our continued development of genomic tools to study these mechanisms in Aiptasia, a small sea anemone with great promise as a model system for studies of cnidarian-dinoflagellate symbiosis. Specifically, we have generated de novo assemblies of the transcriptomes of both a clonal line of symbiotic anemones and their endogenous dinoflagellate symbionts. We then compared transcript abundances in animals with and without dinoflagellates. This analysis identified >900 differentially expressed genes and allowed us to generate testable hypotheses about the cellular functions affected by symbiosis establishment. The differentially regulated transcripts include >60 encoding proteins that may play roles in transporting various nutrients between the symbiotic partners; many more encoding proteins functioning in several metabolic pathways, providing clues as to how the transported nutrients may be used by the partners; and several encoding proteins that may be involved in host recognition and tolerance of the dinoflagellate.G3-Genes Genomes Genetics 12/2013; 4(2). DOI:10.1534/g3.113.009084 · 2.51 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in systemic lupus erythematosus (SLE). However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokine production by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.Journal of Autoimmunity 04/2013; DOI:10.1016/j.jaut.2013.03.002 · 7.02 Impact Factor