Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

ABSTRACT Sindbis virus (SV), an enveloped virus with a single-stranded, plus-sense RNA genome, is the prototype alphavirus in the Togaviridae family. In mice, SV infects neurons and can cause apoptosis of immature neurons. Sphingomyelin (SM) is the most prevalent cellular sphingolipid, is particularly abundant in the nervous systems of mammals, and is required for alphavirus fusion and entry. The level of SM is tightly regulated by sphingomyelinases. A defect in acid sphingomyelinase (ASMase) results in SM storage and subsequent intracellular accumulation of SM. To better understand the role of the SM pathway in SV pathogenesis, we have characterized SV infection of transgenic mice deficient in the ASMase gene. ASMase knockout (ASM-KO) mice were more susceptible to SV infection than wild-type (WT) or heterozygous (Het) animals. Titers of SV were higher in the brains of ASM-KO mice than in the brains of WT mice. More SV RNA was detected by in situ hybridization, more SV protein was detected by immunohistochemistry, and more terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were present in the cortex and hippocampus of ASM-KO mice than in those of WT or Het mice. Interleukin-6 (IL-6), but not IL-1β or tumor necrosis factor alpha, was elevated in infected ASM-KO mice compared to levels in WT or Het mice, but studies with IL-6-KO mice and recombinant SV expressing IL-6 showed no role for IL-6 in fatal disease. Together these data indicate that the increase in susceptibility of ASM-KO mice to SV infection was the result of more-rapid replication and spread of SV in the nervous system and increased neuronal death.

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Role of Tumor Necrosis Factor Alpha (TNF-α) and Interleukin-10 in the Pathogenesis of Severe Murine Monocytotropic Ehrlichiosis: Increased Resistance of TNF Receptor p55- and p75-Deficient Mice to Fatal Ehrlichial Infection

Infection and Immunity ◽

10.1128/iai.74.3.1846-1856.2006 ◽

2006 ◽

Vol 74 (3) ◽

pp. 1846-1856 ◽

Cited By ~ 48

Author(s):

Nahed Ismail ◽

Heather L. Stevenson ◽

David H. Walker

Keyword(s):

Liver Injury ◽

Interleukin 10 ◽

High Dose ◽

Tnf Receptor ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACTIntraperitoneal (i.p.) infection with a high dose of a highly virulentEhrlichiastrain (IOE) results in a toxic shock-like syndrome characterized by severe liver injury and systemic overproduction of tumor necrosis factor alpha (TNF-α) by CD8+T cells. We examined the role of TNF-α and TNF receptors in high-dose-IOE-induced shock/liver injury. TNF receptor (TNFR) I/II−/−mice lacking both the p55 and p75 receptors for this cytokine were more resistant to IOE-induced liver injury than their wild-type background controls. TNFR I/II−/−mice survived longer, dying between 15 and 18 days, with evidence of mild liver necrosis/apoptosis. In contrast, wild-type mice were not rescued from the lethal effect of IOE by TNF-α neutralization. TNF-α-depleted mice developed severe liver injury and succumbed to disease between days 9 and 11 postinfection, similar to sham-treated, infected wild-type mice. Although IFN-γ production in the spleens of IOE-infected TNFR I/II−/−and TNF-α-depleted mice was higher than that detected in wild-type controls, these mice had higher bacterial burdens than infected controls. Following high-dose IOE challenge, TNFR I/II−/−and TNF-α-depleted mice have an early increase in IL-10 levels in sera and spleens, which was produced mainly by adherent spleen cells. In contrast, a late burst of interleukin-10 (IL-10) was observed in control mice. Nonadherent spleen cells were the major source of IL-10 in IOE-infected wild-type mice. We conclude that TNFR I/II and TNF-α participate inEhrlichia-induced shock and host defense by regulating liver injury and controlling ehrlichial burden. Our data suggest that fatal ehrlichiosis could be a multistep process, where TNF-α is not solely responsible for mortality.

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Sex Differences and Drug Dose Influence the Role of the α7 Nicotinic Acetylcholine Receptor in the Mouse Dextran Sodium Sulfate-Induced Colitis Model

Nicotine & Tobacco Research ◽

10.1093/ntr/ntw245 ◽

2016 ◽

Vol 19 (4) ◽

pp. 460-468 ◽

Cited By ~ 6

Author(s):

Shakir D. AlSharari ◽

Deniz Bagdas ◽

Hamid I. Akbarali ◽

Patraic A. Lichtman ◽

Erinn S. Raborn ◽

...

Keyword(s):

Sex Differences ◽

Tumor Necrosis ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Nicotinic Acetylcholine ◽

Male And Female ◽

Factor Alpha ◽

Α7 Nachrs ◽

Necrosis Factor

Abstract Introduction: α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results: Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses. Conclusions: Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse. Implications: Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.

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Interleukin-18 Impairs the Pulmonary Host Response to Pseudomonas aeruginosa

Infection and Immunity ◽

10.1128/iai.71.4.1630-1634.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 1630-1634 ◽

Cited By ~ 50

Author(s):

Marc J. Schultz ◽

Sylvia Knapp ◽

Sandrine Florquin ◽

Jennie Pater ◽

Kiyoshi Takeda ◽

...

Keyword(s):

Inflammatory Responses ◽

Pulmonary Inflammation ◽

Wild Type ◽

Interleukin 18 ◽

Necrosis Factor Alpha ◽

Fusion Construct ◽

Inflammatory Protein ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Interleukin-18 (IL-18) is a potent cytokine with many different proinflammatory activities. To study the role of IL-18 in the pathogenesis of Pseudomonas pneumonia, IL-18-deficient (IL-18 −/−) and wild-type mice were intranasally inoculated with Pseudomonas aeruginosa. IL-18 deficiency was associated with reduced outgrowth of Pseudomonas in the lungs and diminished dissemination of the infection. In addition, pulmonary inflammation (histopathology) and levels of tumor necrosis factor alpha, IL-6, and macrophage inflammatory protein-2 in lungs and plasma were lower in IL-18 −/− mice. Consistent with results obtained for IL-18 −/− mice, treatment of wild-type mice with a neutralizing IL-18 binding protein-immunoglobulin G Fc fusion construct also attenuated outgrowth of Pseudomonas compared with that for mice treated with a control protein. These results demonstrate that the presence of endogenous IL-18 activity facilitates inflammatory responses in the lung during Pseudomonas pneumonia, concurrently impairing bacterial clearance.

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