scholarly journals Intracellular Adhesion Molecule 1 Plays a Key Role in Acquired Immunity to Salmonellosis

2003 ◽  
Vol 71 (10) ◽  
pp. 5881-5891 ◽  
Author(s):  
Simon Clare ◽  
Robert Goldin ◽  
Christine Hale ◽  
Richard Aspinall ◽  
Cameron Simmons ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Critical Role ◽  
Interleukin 2 ◽  
Sublethal Dose ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Intracellular Adhesion Molecule ◽  
Serovar Typhimurium ◽  
Factor Alpha

ABSTRACT This study investigated the role of intracellular adhesion molecule 1 (ICAM-1) during Salmonella enterica serovar Typhimurium infection of mice. We show that ICAM-1 is expressed in and around granulomas on day 4 of infection in wild-type mice. However, when naive ICAM-1−/− mice were challenged with a sublethal dose of serovar Typhimurium, there were no detectable differences in systemic bacterial burden over the first 9 days of infection compared to wild-type control mice. When mice were immunized with the S. enterica serovar Typhimurium vaccine strain SL2361 and then challenged with the virulent S. enterica serovar Typhimurium strain C5, 100% of the ICAM-1−/− mice succumbed to infection, compared to 30% of wild-type mice. T-cell responses, as measured by activation via interleukin-2 production, as well as antibody responses were comparable in the ICAM-1−/− and wild-type mice. Following challenge, counts in organs were significantly higher in the ICAM-1−/− mice, and histological examination of organs showed pathological differences. Strain SL3261-immunized wild-type mice had cellular infiltrate and normal granuloma formation in the liver and spleen on days 5 and 10 after challenge with strain C5. ICAM-1−/− mice had a similar infiltrate on day 5, whereas on day 10 the infiltrate was more widespread and there were fewer macrophages associated with the granulomas. High circulating levels of tumor necrosis factor alpha and gamma interferon, as well as a high burden of strain C5 in the blood, accompanied the differences in histopathology. In this study we show that ICAM-1 plays a critical role during rechallenge of immunized mice with virulent S. enterica serovar Typhimurium.

scholarly journals Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance during Salmonella enterica Serovar Typhimurium Infection

2003 ◽  
Vol 71 (9) ◽  
pp. 4873-4882 ◽  
Author(s):  
Qian Li ◽  
Bobby J. Cherayil
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Peritoneal Macrophages ◽  
Phagocytic Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Serovar Typhimurium ◽  
Tlr4 Gene ◽  
Factor Alpha

ABSTRACT Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-α) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-κB signaling pathways was relatively unaffected, as was increased expression of TNF-α mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-κB p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-α. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-α transcript and at least some genes associated with macrophage tolerance.

scholarly journals The role of endothelial PI3Kγ activity in neutrophil trafficking

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 150-157 ◽  
Author(s):  
Kamal D. Puri ◽  
Teresa A. Doggett ◽  
Ching-Yu Huang ◽  
Jason Douangpanya ◽  
Joel S. Hayflick ◽  
...  
Keyword(s):  
Critical Role ◽  
Fold Increase ◽  
Necrosis Factor Alpha ◽  
Catalytic Subunits ◽  
Injury Model ◽  
Lung Injury Model ◽  
Factor Alpha ◽  
Phosphoinositide 3 Kinase

Phosphoinositide 3-kinase gamma (PI3Kγ) in neutrophils plays a critical role in the directed migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3Kγ activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class-Ib PI3K function in neutrophils of p110γ–/– mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in wild-type (WT) neutrophil attachment to and 17-fold increase in rolling velocities on p110γ–/– microvessels in vivo in response to tumor necrosis factor alpha (TNFα). This alteration in adhesion was further augmented by a deficiency in p110δ, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin–mediated adhesion in p110γ–/– mice was impaired by more than 95%, but no defect in nuclear factor kappa B (NF-κB)–induced gene expression was observed. These findings suggest a previously unrecognized partnership between class-I PI3Ks expressed in leukocytes and endothelium, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation.

scholarly journals iRhom2: An Emerging Adaptor Regulating Immunity and Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6570 ◽  
Author(s):  
Mazin A. Al-Salihi ◽  
Philipp A. Lang
Keyword(s):  
Critical Role ◽  
Growth Factor Receptor ◽  
Biologically Active ◽  
Necrosis Factor Alpha ◽  
Dna Viruses ◽  
Catalytic Center ◽  
Intramembrane Proteases ◽  
Epidermal Growth ◽  
Factor Alpha

The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFα), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling. Accordingly, with iRhom2 having a profound influence on ADAM17 activation and substrate specificity it regulates these signaling pathways. Moreover, iRhom2 has a role in the innate immune response to both RNA and DNA viruses and in regulation of keratin subtype expression in wound healing and cancer. Here we review the role of iRhom2 in immunity and disease, both dependent and independent of its regulation of ADAM17.

scholarly journals The Chemokine CCL2 Is Required for Control of Murine Gastric Salmonella enterica Infection

2005 ◽  
Vol 73 (10) ◽  
pp. 6514-6522 ◽  
Author(s):  
R. William DePaolo ◽  
Rashida Lathan ◽  
Barrett J. Rollins ◽  
William J. Karpus
Keyword(s):  
Typhoid Fever ◽  
Salmonella Enterica ◽  
Critical Factor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Vitro Analysis ◽  
In Vitro Analysis

ABSTRACT Salmonella enterica is a gram-negative intracellular pathogen that can cause a variety of diseases ranging from gastroenteritis to typhoid fever. The Typhimurium serotype causes gastroenteritis in humans; however, infection of mice results in an enteric fever that resembles human typhoid fever and has been used as a model for typhoid fever. The present study examined the role of the chemokine CCL2 in the control of Salmonella infection. Upon infection with salmonellae, mucosal expression of CCL2 is rapidly up-regulated, followed by systemic expression in the spleen. CCL2−/− mice became moribund earlier and had a higher rate of mortality compared to wild-type C57BL/6 mice. Moreover, CCL2−/− mice had significantly higher levels of bacteria in the liver compared to wild-type controls. Mucosal and serum interleukin-6 and tumor necrosis factor alpha levels were elevated in CCL2−/− mice compared to wild-type mice. In vitro analysis demonstrated that CCL2−/− macrophages infected with salmonellae resulted in dysregulated cytokine production compared to macrophages derived from wild-type mice. These data are the first to directly demonstrate CCL2 as a critical factor for immune responses and survival following S. enterica infection.

scholarly journals Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

2006 ◽  
Vol 80 (22) ◽  
pp. 10989-10999 ◽  
Author(s):  
Ching G. Ng ◽  
Diane E. Griffin
Keyword(s):  
Sindbis Virus ◽  
Acid Sphingomyelinase ◽  
Wild Type ◽  
Fatal Disease ◽  
Necrosis Factor Alpha ◽  
Enveloped Virus ◽  
Factor Alpha ◽  
Necrosis Factor

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.

scholarly journals Disruption of the Genes for ClpXP Protease in Salmonella enterica Serovar Typhimurium Results in Persistent Infection in Mice, and Development of Persistence Requires Endogenous Gamma Interferon and Tumor Necrosis Factor Alpha

2001 ◽  
Vol 69 (5) ◽  
pp. 3164-3174 ◽  
Author(s):  
Tomoko Yamamoto ◽  
Hiroshi Sashinami ◽  
Akiko Takaya ◽  
Toshifumi Tomoyasu ◽  
Hidenori Matsui ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Type Strain ◽  
Tumor Necrosis ◽  
Wild Type Strain ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Serovar Typhimurium ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT The enteric pathogen Salmonella enterica serovar Typhimurium, similar to other facultative intracellular pathogens, has been shown to respond to the hostile conditions inside macrophages of the host organism by producing a set of stress proteins that are also induced by various environmental stresses. The stress-induced ClpXP protease is a member of the ATP-dependent proteases, which are known to be responsible for more than 90% of all proteolysis inEscherichia coli. To investigate the contribution of the ClpXP protease to the virulence of serovar Typhimurium we initially cloned the clpP and clpX operon from the pathogenic strain serovar Typhimurium χ3306 and then created insertional mutations in the clpP and/or clpXgene. The ΔclpP and ΔclpX mutants were used to inoculate BALB/c mice by either the intraperitoneal or the oral route and found to be limited in their ability to colonize organs of the lymphatic system and to cause systemic disease in the host. A variety of experiments were performed to determine the possible reasons for the loss of virulence. An oxygen-dependent killing assay using hydrogen peroxide and paraquat (a superoxide anion generator) and a serum killing assay using murine serum demonstrated that all of the serovar Typhimurium ΔclpP and ΔclpX mutants were as resistant to these killing mechanisms as the wild-type strain. On the other hand, the macrophage survival assay revealed that all these mutants were more sensitive to the intracellular environment than the wild-type strain and were unable to grow or survive within peritoneal macrophages of BALB/c mice. In addition, it was revealed that the serovar Typhimurium ClpXP-depleted mutant was not completely cleared but found to persist at low levels within spleens and livers of mice. Interferon gamma-deficient mice and tumor necrosis factor alpha-deficient mice failed to survive the attenuated serovar Typhimurium infections, suggesting that both endogenous cytokines are essential for regulation of persistent infection with serovar Typhimurium.

scholarly journals 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

2006 ◽  
Vol 74 (3) ◽  
pp. 1846-1856 ◽  
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.

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

2016 ◽  
Vol 19 (4) ◽  
pp. 460-468 ◽  
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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