ReviewTWEAK/Fn14 axis: The current paradigm of tissue injury-inducible function in the midst of complexities
Introduction
Tissue injury triggers the response of tissue-resident cell types to address the injury-imposed cellular stress and damage. Tissue responses occur quickly after acute injury and comprise a well-orchestrated series of events including the production of growth factors and cytokines to promote parenchymal cell survival and growth, recruitment of inflammatory cells, angiogenesis, and fibrogenic responses. Importantly, infiltrating leukocytes act both to remove cellular and foreign debris and activate progenitor cells, thereby promoting tissue repair and regeneration. Angiogenic sprouting generates blood vessels bringing nutrients to newly formed and healing tissue, and fibrogenic responses mediate the controlled activation of connective tissue cells that produce new and temporary extracellular matrix (ECM) to stabilize and guide the remodeling tissue. Both the manifestation and fine coordination of these processes is critical for physiological tissue repair and healing. However, robust acute, repetitious, and chronic insults can perturb and dysregulate the orchestration of these events, and as such, chronic wound healing processes pose serious challenges for normal tissue repair and regeneration, with potential pathophysiological outcomes including functional tissue loss due to cell death, degeneration, atrophy, and metabolic dysfunction. In addition, excessive fibrogenic and impeded progenitor cell responses may tip the balance to myofibroblasts, the major collagen-producing cell type in injured tissue, thereby resulting in tissue fibrosis, the excessive deposition of ECM that replaces lost tissue and collagen crosslinking which increases tissue stiffness, thereby compromising organ function. These detrimental, tissue-damaging and -remodeling outcomes are featured in many chronic autoimmune and inflammatory diseases and are key determinants of the long-term prognosis of these diseases, posing significant medical issues due to the loss of organ function. Notably, processes resembling those in chronic wound healing are also featured in tissues with malignancy, including the expression of factors that support the tumor growth directly and through the establishment of tumor microenvironments containing inflammatory infiltrates, new blood vessels, and progressive tumor-stromal cell reactions comprised of connective tissue cells and newly produced ECM [1], [2].
Insight into the current paradigm of the TWEAK/Fn14 pathway as a tissue injury-responsive pathway and its functional dichotomy in regulating physiological versus pathophysiological tissue responses has evolved tremendously since the late 1990s. Seminal discoveries in the unfolding of this paradigm were those of TWEAK, first described in 1997 as a constitutively expressed TNF family ligand in macrophages [3], followed in 2001 by the expression cloning of its only known signaling receptor, shown to be identical to the previously reported fibroblast growth factor inducible molecule 14, Fn14 [4], [5]. Clues as to the locale and timing of TWEAK/Fn14 engagement constituted other major milestones, namely the awareness of leukocytes as a major source of TWEAK and the extensive body of work informing the relatively low level of Fn14 expression in normal healthy tissues but highly inducible pattern of Fn14 expression locally in injured and diseased tissues [6], [7]. Fn14 is expressed transiently in acutely injured tissues and persistently in chronically injured where it is disease tissues, where it is broadly expressed in architectural cell types including parenchymal, vascular and stromal cells, and notably also tissue progenitor cells. In addition, mirroring sustained Fn14 expression in chronically diseased tissues, Fn14 was shown to be constitutively expressed in many solid tumors [7]. In the light of these key findings and in vivo studies in animal models of acute versus chronic injury and disease, the pleiotropic activities induced by the diverse TWEAK/Fn14 pathway signaling potentials, including the activation of NFκB, MAPK, PI3K/Akt and/or other downstream pathways, have come to be understood as components of a multi-dimensional injury-induced tissue response, with functional dichotomy in acute versus chronic injury/disease settings [6], [8]. Whereas the TWEAK/Fn14 pathway has the potential to promote productive tissue responses when transiently engaged after acute injury through its ability to orchestrate controlled, acute inflammatory, angiogenic and fibrogenic responses, and regulate parenchymal cell survival and growth and endogenous tissue progenitor responses, the excessive or persistent activation of the TWEAK/Fn14 pathway in chronic injury/disease can exaggerate and dysregulate these events, thereby driving progressive detrimental, tissue damaging and pathological tissue remodeling outcomes (Fig. 1).
This review addresses the current paradigm for the tissue injury-induced functions of the TWEAK/Fn14 pathway, first highlighting recent advances in understandings of the complexity of TWEAK/Fn14 signaling potentials and how the spatial and temporal modes of signaling may differentially affect functional outcomes. The paradigm of functional dichotomy in physiological versus pathophysiological tissue injury responses is then further developed, addressing the pathological roles of the TWEAK/Fn14 axis in chronic inflammatory and fibrotic diseases and cancer.
Section snippets
TWEAK and Fn14 expression
TWEAK is a typical TNF superfamily member, synthesized as a type II transmembrane protein in the endoplasmic reticulum and expressed as a homotrimeric molecule. Immune cells types appear to be a prominent source of TWEAK, with TWEAK mRNA broadly expressed by cells of hematopoietic lineage (Immunological Genome Project Consortium, Datagroup Human Immune Cells Garvan, Gene Symbol TNFSF12, Probe set 205611_at) and intracellular TWEAK protein detected in human resting and activated monocytes,
Functional dichotomy in acute versus chronic tissue injury
Currently available data fit the paradigm that TWEAK, produced primarily by leukocytes, engages injury-induced, locally expressed Fn14 on tissue-resident epithelial, endothelial, and stromal cell types, inducing pleiotropic activities that comprise a response to tissue injury [8]. After acute injury, Fn14 is transiently upregulated, resulting in productively orchestrated cellular responses, including acute inflammation and controlled angiogenic and fibrogenic responses. Indeed, the beneficial
Role of TWEAK in cancer
Cancer initiation, tumor growth and metastasis are multistep processes that are dictated by genetic changes and the balance of pro-tumoral and anti-tumoral pathways. Tumors and their complex microenvironments feature growth factors that support the survival, proliferation and migration of the malignant cells, new blood vessel formation to feed the growing tumor, inflammatory infiltrates including tumor-promoting M2 macrophages, and progressive tumor-stromal cell reactions comprised of
Conclusion
While acute tissue injury triggers a well-orchestrated tissue repair response, chronic tissue injury features dysregulated and unresolved wound healing processes, including growth factor and proinflammatory mediator expression, immune cell infiltration, angiogenesis, myofibroblast generation and collagen deposition, in the target tissues of chronic inflammatory diseases that are mimicked in tissues with malignancy. Indeed, the TWEAK/Fn14 pathway has emerged as a key, tissue injury-induced
Acknowledgement
Dr. Nicolas Wisniacki, Biogen Idec, provided expert review and critical comments.
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