D-Galactosamine lethality model: scope and limitations

176

153

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPSassociated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade. autoinflammatory disease | genetic disease

Section: Enhanced Lethality Of Lps In Heterozygous Traps-mutant Tnfr1mentioning

confidence: 99%

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Simon¹,

Park

Maddipati

et al. 2010

176

153

“…The major difference between the studies is the use of D-GalN. D-GalN not only increases toxic metabolites of uracil nucleotides in liver cells but also sensitizes liver cells to TNF (26). Because D-GalN is more toxic in adult mouse liver (Fig.…”

Section: 01) Data Are Presented As Mean Values (ϯSem) (D) Lethal mentioning

confidence: 99%

“…We reasoned that the different outcomes of LPS/D-GalN and LPS models might reside in D-GalN, a sensitizer of liver damage and lethality induced by endotoxin, superantigen, lipoprotein, or bacteria (26). Because the toxic effects of D-GalN in hosts of different ages have not been well defined, we analyzed the hepatotoxicity of D-GalN in neonatal and adult mice.…”

Section: D-galn Induced More Severe Hepatotoxicity In Adult Mice Than Inmentioning

confidence: 99%

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

146

129

Neonates suffer high morbidity and mortality in infection, presumably because of the lack of a fully developed adaptive and innate immune system. Evidence of poor innate responses in neonates has been shown by using a model that sensitizes the host to Toll-like receptor (TLR)-mediated inflammation with D-galactosamine (DGalN). However, we show that neonatal mice demonstrate much stronger inflammatory responses than adult mice in response to LPS stimulation, and such hypersensitivity extends to other TLR agonists including actual viral infection. Our study reveals that the ensuing inflammatory reaction after D-GalN sensitization reflects preferential toxicity of D-GalN to adult liver cells, rather than accurately reflecting the TLR response to LPS. We show further that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection. Remarkably, through transfer of T cells into neonates or depletion of T cells in adult mice, we show that T cells are sufficient and necessary to control the early inflammatory response to LPS. Therefore, neonates might suffer from the unleashed innate responses caused by an insufficient number of T cells, which leads to increased morbidity and mortality.

“…Two models were tested: (i) WT and tamLITAF(i) −/− mice were subjected to a model of lethal TNF-α sensitization by pretreatment with D-GalN, a known factor that sensitizes mice to the lethal effects of LPS and causes death due to TNF-α toxicity (16,17). The D-GalN was followed by an i.p.…”

Section: Survival Rates Of Lps-induced Endotoxin Challenge In Tamlitamentioning

confidence: 99%

“…Nonetheless, only partial protection from LPS-induced lethal endotoxic shock was achieved. We questioned whether an extension of LITAF deficiency to other LITAF-producing cells in addition to macrophages would improve protection against the deleterious effects of inflammation (16).…”

mentioning

confidence: 99%

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Merrill

You

Constable

et al. 2011

LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that macrophage-specific LITAF-deficient (macLITAF −/− ) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cytokines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLITAF(i)] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (i) tamLITAF(i) −/− mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF −/− mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i) −/− mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i) −/− mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease-namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.septic shock | multiplex