The TNF-like weak inducer of the apoptosis/fibroblast growth factor–inducible molecule 14 axis mediates histamine and platelet-activating factor–induced subcutaneous vascular leakage and anaphylactic shock

Abstract

Background: Anaphylaxis includes mast cell (MC) activation, but less is known about downstream mechanisms (ie, vascular permeability controlled by endothelial cells [ECs]). The TNFlike weak inducer of apoptosis (TWEAK) and its sole receptor, fibroblast growth factor-inducible molecule 14 (Fn14), belong to the TNF superfamily and are involved in proinflammatory responses. Objective: We sought to investigate the role of TWEAK/Fn14 axis in anaphylaxis. Methods: In vivo vascular permeability and mouse models of passive systemic anaphylaxis (PSA) and active systemic anaphylaxis were applied to wild-type (WT), TWEAK-and Fn14-deficient mice (TWEAK 2/2 and Fn14 2/2 , respectively). Primary bone marrow-derived mast cells (BMMCs) and ECs from WT and Fn14 2/2 or TWEAK 2/2 mice were studied. The TWEAK/Fn14 axis was also investigated in human samples. Results: Mice with PSA and active systemic anaphylaxis had increased Fn14 and TWEAK expression in lung tissues and increased serum soluble TWEAK concentrations. TWEAK and Fn14 deficiencies prevent PSA-related symptoms, resulting in resistance to decreased body temperature, less severe reactions, and maintained physical activity. Numbers of MCs after PSA are similar between genotypes in different tissue regions, such as ear skin and the trachea, tongue, peritoneum, lungs, and bone marrow. Moreover, in vitro studies revealed no differences in degranulation or mediator release between WT and Fn14 2/2 BMMCs after IgE-FcεRI stimulation. In vivo and in vitro histamine and platelet-activating factor administration increases Fn14 receptor expression in lungs and ECs. Moreover, Fn14 deficiency in ECs maintained in vitro impermeability when stimulated by mediators or activated BMMCs but not by TWEAK 2/2 BMMCs, indicating that Fn14 is crucial for endothelial barrier function. TWEAK/Fn14 deletion or TWEAK-blocking antibody prevented histamine/plateletactivating factor-induced vascular subcutaneous permeability. Circulating soluble TWEAK levels were increased in patients with anaphylaxis, and plasma from those patients increased Fn14 expression in ECs. Conclusion: The TWEAK/Fn14 axis participates in anaphylactic reactions. Inhibition of TWEAK/Fn14 interaction could be efficacious in anaphylaxis therapy.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges

“…Furthermore, Fn14 expression is induced by fetal bovine serum, EGF, FGF-1, FGF-2, PDGF-BB, in murine and human fibroblast in vitro [6]. Fn14 is also upregulated in human CD14+ monocytes by INF-γ or PMA [27] and in primary BMMCs by anti-DNP IgE sensitization followed by DNP challenge [28]. However, Fn14 expression is absent in T and B lymphocytes [34].…”

“…At the cellular level, TWEAK is expressed in various immune cell types, including macrophages [7], microglia [24], activated monocytes and T cells [25,26], dendritic cells, natural killer (NK) cells [27], and mast cells [28]. In addition, macrophages/monocytes are the main source of sTWEAK in inflammatory tissues [29].…”

“…Moreover, Fn14 mRNA is also detected in cardiac fibroblasts [32]. TWEAK protein secretion can be upregulated by PMA and INF-γ in cultured human peripheral mononuclear cells [27] and in natural killer cells [26] and by anti-DNP Immunoglobulin E (IgE) sensitization followed by DNP challenge in bone marrow-derived mast cells (BMMCs) [28]. In addition, Fn14 expression is upregulated under pathological conditions by several growth factors, cytokines and interleukins.…”

“…Thus, Fn14 expression is increased by pro-inflammatory cytokines (IL-1B and INF-γ), growth factors (PDGF-BB, EGF, FGF-2), angiotensin II, or α-thrombin [11,18] in human and rat aortic SMCs. Moreover, Fn14 expression is upregulated in human umbilical endothelial cells by VEGF-A and FGF-2 [33], and in mouse aortic endothelial cells by histamine and the platelet-activator factor (PAF) [28]. In neonatal rat cardiomyocytes, Fn14 expression is induced by fibroblast growth factor 1 (FGF-1), norepinephrine, angiotensin II, and mechanical stretch via the Rho/ROCK pathway [30].…”

The TWEAK/Fn14 axis in anaphylactic shock

“…[1][2][3] Given the serious threat posed by anaphylaxis, considerable effort has gone into attempting to explain the phenomenon mechanistically, ideally in a way that also suggests how to improve therapy. In this issue of the Journal, Mendez-Barbero et al 4 describe, primarily on the basis of studies in mice, the involvement in anaphylaxis of the TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor, the fibroblast growth factor-inducible molecule 14 (Fn14). TWEAK, which can be produced by monocytes and many other cells, 5 has been shown to contribute to skin inflammation in mouse models of atopic dermatitis and psoriasis.…”