LIGHT aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway.

Sepsis-associated acute kidney injury (SA-AKI) is a common clinical critical care syndrome. It has received increasing attention due to its high morbidity and mortality; however, its pathophysiological mechanisms remain elusive. LIGHT, the 14th member of the tumour necrosis factor (TNF) superfamily and a bidirectional immunoregulatory molecule that regulates inflammation, plays a pivotal role in disease pathogenesis. In this study, mice with an intraperitoneal injection of LPS and HK-2 cells challenged with LPS were employed as a model of SA-AKI in vivo and in vitro, respectively. LIGHT deficiency notably attenuated kidney injury in pathological damage and renal function and markedly mitigated the inflammatory reaction by decreasing inflammatory mediator production and inflammatory cell infiltration in vivo. The TLR4-Myd88-NF-κB signalling pathway in the kidney of LIGHT knockout mice was dramatically down-regulated compared to the controls. Recombinant human LIGHT aggravated LPS-treated HK-2 cell injury by up-regulating the expression of the TLR4-Myd88-NF-κB signalling pathway and inflammation levels. TAK 242 (a selective TLR4 inhibitor) reduced this trend to some extent. In addition, blocking LIGHT with soluble receptor fusion proteins HVEM-Fc or LTßR-Fc in mice attenuated renal dysfunction and pathological damage in SA-AKI. Our findings indicate that LIGHT aggravates inflammation and promotes kidney damage in LPS-induced SA-AKI via the TLR4-Myd88-NF-κB signalling pathway, which provide potential strategies for the treatment of SA-AKI.

LIGHT-HVEM signaling in keratinocytes controls development of dermatitis.

Dermatitis is often associated with an allergic reaction characterized by excessive type 2 responses leading to epidermal acanthosis, hyperkeratosis, and dermal inflammation. Although factors like IL-4, IL-13, and thymic stromal lymphopoietin (TSLP) are thought to be instrumental for the development of this type of skin disorder, other cytokines may be critical. Here, we show that the tumor necrosis factor (TNF) superfamily protein LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes) is required for experimental atopic dermatitis, and LIGHT directly controls keratinocyte hyperplasia, and production of periostin, a matricellular protein that contributes to the clinical features of atopic dermatitis as well as other skin diseases such as scleroderma. Mice with a conditional deletion of the LIGHT receptor HVEM (herpesvirus entry mediator) in keratinocytes phenocopied LIGHT-deficient mice in exhibiting reduced epidermal thickening and dermal collagen deposition in a model of atopic dermatitis driven by house dust mite allergen. LIGHT signaling through HVEM in human epidermal keratinocytes directly induced proliferation and periostin expression, and both keratinocyte-specific deletion of HVEM or antibody blocking of LIGHT-HVEM interactions after disease onset prevented expression of periostin and limited atopic dermatitis symptoms. Developing reagents that neutralize LIGHT-HVEM signaling might be useful for therapeutic intervention in skin diseases where periostin is a central feature.

Impairment of Bone Remodeling in LIGHT/TNFSF14-Deficient Mice.

Multiple cytokines produced by immune cells induce remodeling and aid in maintaining bone homeostasis through differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we investigate bone remodeling controlled by the tumor necrosis factor (TNF) superfamily cytokine LIGHT. LIGHT-deficient mice (Tnfsf14-/- ) exhibit spine deformity and reduced femoral cancellous bone mass associated with an increase in the osteoclast number and a slight decrease of osteoblasts compared with WT mice. The effect of LIGHT in bone cells can be direct or indirect, mediated by both the low expression of the anti-osteoclastogenic osteoprotegerin (OPG) in B and T cells and reduced levels of the pro-osteoblastogenic Wnt10b in CD8+ T cells in Tnfsf14-/- mice. LIGHT stimulation increases OPG levels in B, CD8+ T, and osteoblastic cells, as well as Wnt10b expression in CD8+ T cells. The high bone mass in Light and T- and B-cell-deficient mice (Rag- /Tnfsf14- ) supports the cooperative role of the immune system in bone homeostasis. These results implicate LIGHT as a potential target in bone disease. © 2017 American Society for Bone and Mineral Research.

Deficiency of LIGHT signaling pathway exacerbates Chlamydia psittaci respiratory tract infection in mice.

LIGHT, a costimulatory member of the immunoglobulin superfamily (Ig SF), can greatly impact T cell activation. The role of the LIGHT signaling pathway in chlamydial infection was evaluated in mice following respiratory tract infection with Chlamydia psittaci. Compared with wild type (WT) mice, LIGHT knockout (KO) mice showed significant reduction of body weight, much lower survival rate, higher bacterial burden, prolonged infection time courses and more severe pathological changes in lung tissue. The mRNA levels of IFN-γ, TNF-α, IL-17 and IL-12 in the lung tissue of LIGHT KO mice were significantly lower than those in WT mice. While there was no obvious difference in the percentages of CD4+ and CD8+ T cells in the spleens of the two groups of mice, there was a markedly elevated percentage of CD4+ CD25+ FoxP3+ Treg cells in LIGHT KO mice. Together, these results demonstrate that the LIGHT signaling pathway is not only required for inflammatory cytokine production as part of the host response to chlamydial infection, but also influences the differentiation of CD4+ CD25+ FoxP3+ Treg cells, both of which may be essential for control of C. psittaci respiratory tract infection.

The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis.

Several inflammatory diseases including scleroderma and atopic dermatitis display dermal thickening, epidermal hypertrophy, or excessive accumulation of collagen. Factors that might promote these features are of interest for clinical therapy. We previously reported that LIGHT, a TNF superfamily molecule, mediated collagen deposition in the lungs in response to allergen. We therefore tested whether LIGHT might similarly promote collagen accumulation and features of skin fibrosis. Strikingly, injection of recombinant soluble LIGHT into naive mice, either subcutaneously or systemically, promoted collagen deposition in the skin and dermal and epidermal thickening. This replicated the activity of bleomycin, an antibiotic that has been previously used in models of scleroderma in mice. Moreover skin fibrosis induced by bleomycin was dependent on endogenous LIGHT activity. The action of LIGHT in vivo was mediated via both of its receptors, HVEM and LTßR, and was dependent on the innate cytokine TSLP and TGF-ß. Furthermore, we found that HVEM and LTßR were expressed on human epidermal keratinocytes and that LIGHT could directly promote TSLP expression in these cells. We reveal an unappreciated activity of LIGHT on keratinocytes and suggest that LIGHT may be an important mediator of skin inflammation and fibrosis in diseases such as scleroderma or atopic dermatitis.

The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice.

BACKGROUND & AIMS: The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice. METHODS: We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT. RESULTS: After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin ß receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon. CONCLUSIONS: Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin ß receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation.

LIGHT (TNFSF14/CD258) is a decisive factor for recovery from experimental autoimmune encephalomyelitis.

The TNF superfamily ligand LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator [HVEM], a receptor expressed by T lymphocytes) has been shown to play a role in T cell costimulation and be involved in apoptosis of mononuclear cells. As both T cells and monocytes are key components in the development and progression of experimental autoimmune encephalomyelitis (EAE), we studied the role of LIGHT in EAE. Following immunization with myelin oligodendrocyte glycoprotein peptide (35-55), LIGHT-deficient mice developed severe EAE that resulted in an atypically high mortality rate. Histological examinations revealed intensive activation of microglia/macrophages in the CNS and higher numbers of apoptotic cells within the CNS parenchyma of LIGHT-deficient mice. However, myelin oligodendrocyte glycoprotein peptide-specific CD4(+) T cells from LIGHT-deficient mice showed reduced IFN-γ and IL-17 production and migration. Serum levels of reactive nitrogen intermediates and CNS transcripts of several proinflammatory cytokines and chemokines were also substantially decreased in the absence of LIGHT. EAE adoptive transfer experiments and bone marrow chimeras indicated that expression of LIGHT on donor cells is not required for disease induction. However, its expression on CNS host cells is a decisive factor to limit disease progression and tissue damage. Together, these data show that LIGHT expression is crucially involved in controlling activated macrophages/microglia during autoimmune CNS inflammation.

The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling.

Individuals with chronic asthma show a progressive decline in lung function that is thought to be due to structural remodeling of the airways characterized by subepithelial fibrosis and smooth muscle hyperplasia. Here we show that the tumor necrosis factor (TNF) family member LIGHT is expressed on lung inflammatory cells after allergen exposure. Pharmacological inhibition of LIGHT using a fusion protein between the IgG Fc domain and lymphotoxin ß receptor (LTßR) reduces lung fibrosis, smooth muscle hyperplasia and airway hyperresponsiveness in mouse models of chronic asthma, despite having little effect on airway eosinophilia. LIGHT-deficient mice also show a similar impairment in fibrosis and smooth muscle accumulation. Blockade of LIGHT suppresses expression of lung transforming growth factor-ß (TGF-ß) and interleukin-13 (IL-13), cytokines implicated in remodeling in humans, whereas exogenous administration of LIGHT to the airways induces fibrosis and smooth muscle hyperplasia, Thus, LIGHT may be targeted to prevent asthma-related airway remodeling.

LIGHT contributes to early but not late control of Mycobacterium tuberculosis infection.

The TNF superfamily member, LIGHT, contributes to optimal T-cell activation in vitro through co-stimulation of dendritic cell cytokine production; however, its role in T-cell-mediated control of intracellular bacterial infections is unknown. Protective immunity against Listeria monocytogenes and Mycobacterium tuberculosis infection requires both antigen-specific CD4(+) and CD8(+) T cells. Using LIGHT-deficient mice we determined that LIGHT was necessary for optimal re-stimulation of anti-listerial CD8(+) T cells in vitro. By contrast, LIGHT(-/-) mice infected with L. monocytogenes generated equivalent T-cell responses and controlled the infection as effectively as normal C57BL/6 mice. Following M. tuberculosis infection, LIGHT(-/-) mice showed a significant increase in bacterial replication in the lungs at 4 weeks, but by 6 weeks had controlled the infection. Analysis of T-cell responses in vivo revealed that LIGHT was dispensable for the activation of primary T-cell responses and the production of IL-12 and IFN-gamma. In addition, LIGHT was not required for the induction of memory T-cell responses to anti-mycobacterial DNA or BCG vaccines and for subsequent protection against tuberculosis challenge. Therefore, LIGHT contributes to the optimal co-stimulation of anti-listerial CD8(+) T-cell responses in vitro and to the early control of M. tuberculosis infection; however, other mechanisms compensate for LIGHT deficiency in the control of these pathogens in vivo.

BAFF induces a hyper-IgA syndrome in the intestinal lamina propria concomitant with IgA deposition in the kidney independent of LIGHT.

BAFF is a peripheral B cell survival factor and can mediate antibody (Ab) class switching. Over-expression of BAFF in mice results in B cell hyperplasia, elevated serum immunoglobulin (Ig), spontaneous germinal centre (GC) reactions and mild glomerulonephritis (GN). Here we show that, in addition to driving excessive levels of serum IgA, BAFF over-expression results in increased IgA levels within the intestinal lamina propria (LP) and deposition of IgA immune complexes in the renal glomerular mesangium. LIGHT has been previously shown to mediate a similar phenotype via signaling through the lymphotoxin-beta receptor (LTbetaR). We evaluated if LIGHT and BAFF cooperate in the etiology of a hyper-IgA syndrome in BAFF-overexpressing transgenic (BAFF-Tg) mice. We find that LIGHT-deficient BAFF-Tg mice exhibit similar levels of IgA in the serum, gut and kidney and develop nephritis to the same degree as LIGHT-sufficient BAFF-Tg mice. Therefore, in the context of BAFF over-expression, LIGHT is dispensable for the generation of a hyper-IgA syndrome accompanied by nephritis.