Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells

Herring, Amy C.; Falkowski, Nicole R.; Chen, Gwo Hsiao; McDonald, Rod A.; Toews, Galen B.; Huffnagle, Gary B.

doi:10.1128/iai.73.1.39-49.2005

Cited by 62 publications

(92 citation statements)

References 52 publications

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“…28 As expected, periodic acid-Schiff (PAS) staining of C57BL/6J lungs 35 days after experimental infection demonstrated an allergic bronchopulmonary response characterized by heightened goblet cell metaplasia and airway epithelial mucus accumulation in association with abundant C. neoformans yeast (Figure 1b). 34,35 In comparison, CBA/J exhibited less apparent cryptococci, the absence of an allergic response and greater airway epithelial hypertrophy (Figure 1b). Together, these observations validate our experimental C. neoformans infection model and directly confirm previous reports of an allergic Th2 phenotype among susceptible C57BL/6J mice that contrasts with the Th1-cell-mediated response of the resistant CBA/J strain.…”

Section: Resultsmentioning

confidence: 98%

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

et al. 2008

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Cryptococcus neoformans is a major cause of fungal pneumonia, meningitis and disseminated disease in the immune compromised host. Here we have used a clinically relevant model to investigate the genetic determinants of susceptibility to progressive cryptococcal pneumonia in C57BL/6J and CBA/J inbred mice. At 5 weeks after infection, the lung fungal burden was over 1000-fold higher in C57BL/6J compared to CBA/J mice. A genome-wide scan performed on 210 male and 203 female (CBA/J Â C57BL/6J) F2 progeny using lung colony-forming units as a quantitative trait revealed a sex difference in genetic architecture with three loci (designated Cnes1-Cnes3) associated with susceptibility to cryptococcal pneumonia. Single locus analysis identified significant loci on chromosomes 3 (Cnes1) and 17 (Cnes2) with logarithm of the odds (LOD) scores of 4.09 (P ¼ 0.0110) and 7.30 (Po0.0001) that explained 8.9 and 15.9% of the phenotypic variance, respectively, in female CBAB6F2 and one significant locus on chromosome 17 (Cnes3) with a LOD score of 4.04 (P ¼ 0.010) that explained 8.6% of the phenotypic variance in male CBAB6F2 mice. Genome-wide pair-wise analysis revealed significant quantitative trait locus interactions in both the female and male CBAB6F2 progeny that collectively explained 43.8 and 19.5% of phenotypic variance in each sex, respectively.

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Section: Resultsmentioning

confidence: 98%

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

et al. 2008

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“…The results of our kinetic analysis suggest that ExMs are the predominant macrophage source of these effector molecules because both iNOS and TNF-␣ are significantly diminished in CCR2-deficient mice in which ExMs are scarce. Previous investigations 12,18,23,[62][63][64][65][66][67] have defined iNOS and TNF-␣ expression as strong predictors of cryptococcal killing in vitro and clearance of the organism in vivo, although other effector mechanisms may also contribute to ExM fungicidal activity. Additional studies are also required to understand whether and how these cells interact with other critical leukocyte populations that we have previously identified, including DCs and IFN-␥-producing T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Visual inspection of cytospins prepared from sorted populations confirmed that both AMs and ExMs were large cells (12)(13)(14)(15)(16)(17)(18) m) with abundant cytoplasm and round/oval nuclei ( Figure 1D). AMs displayed largely smooth cell membranes and contained few intracellular vacuoles.…”

Section: Cd11c ϩ Cd11b ϩ Autofluorescent Exms Are the Most Prevalent mentioning

confidence: 95%

“…Second, we evaluated the expression of two molecules iNOS and TNF-␣, that are critically important in mediating antifungal host defense. 12,18,23,[62][63][64][65][66][67] Whole lung mRNA expression of iNOS and TNF-␣ was similar in uninfected CCR2 ϩ/ϩ mice and CCR2 Ϫ/Ϫ mice (data not shown). However, the expression of iNOS and TNF-␣ was significantly increased in CCR2 ϩ/ϩ mice relative to CCR2 Ϫ/Ϫ mice at 14 dpi ( Figure 8A).…”

Section: Exms Are Classically Activated and Fungicidalmentioning

confidence: 99%

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Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

Osterholzer

Chen

Olszewski

et al. 2011

The American Journal of Pathology

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112

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Clearance of pulmonary infection with the fungal pathogen Cryptococcus neoformans is associated with the accumulation and activation of lung macrophages. However, the phenotype of these macrophages and the mechanisms contributing to their accumulation are not well-defined. In this study, we used an established murine model of cryptococcal lung infection and flow cytometric analysis to identify alveolar macrophages (AMs) and the recently described exudate macrophages (ExMs). Exudate macrophages are distinguished from AMs by their strong expression of CD11b and major histocompatibility complex class II and modest expression of costimulatory molecules. Exudate macrophages substantially outnumber AMs during the effector phase of the immune response; and accumulation of ExMs, but not AMs, was chemokine receptor 2 (CCR2) dependent and attributable to the recruitment and subsequent differentiation of Ly-6C high monocytes originating from the bone marrow and possibly the spleen. Peak ExM accumulation in wild-type (CCR2 ؉/؉ ) mice coincided with maximal lung expression of mRNA for inducible nitric oxide synthase and correlated with the known onset of cryptococcal clearance in this strain of mice. Exudate macrophages purified from infected lungs displayed a classically activated effector phenotype characterized by cryptococcal-enhanced production of inducible nitric oxide synthase and tumor necrosis factor ␣. Cryptococcal killing by bone marrow-derived ExMs was CCR2 independent and superior to that of AMs. We conclude that clearance of cryptococcal lung infection requires the CCR2-mediated massive accumulation of fungicidal ExMs derived from circulating Ly-6C high monocytes.

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“…Neutrophils were depleted by i.p. injection of 0.25 mg of anti-Gr1 (RB6-8C5) (18). IL-12 was neutralized by i.p.…”

Section: Media Cytokines and Neutralizing Absmentioning

confidence: 99%

The Role of Dendritic Cells in the Development of Acute Dextran Sulfate Sodium Colitis

Berndt¹,

Zhang²,

Chen

et al. 2007

The Journal of Immunology

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129

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Dendritic cells (DCs) are essential mediators of the host immune response to surrounding microbes. In this study, we investigate the role of DCs in the pathogenesis of a widely used colitis model, dextran sulfate sodium-induced colitis. The effect of dextran sulfate sodium on the production of proinflammatory cytokines and chemokines by bone marrow-derived DCs (BM-DCs) was analyzed. BM-DCs were adoptively transferred into C57BL/6 mice or DCs were ablated using transgenic CD11c-DTR/GFP mice before treatment with 5% dextran sulfate sodium in drinking water. We found that dextran sulfate sodium induced production of proinflammatory cytokines (IL-12 and TNF-α) and chemokines (KC, MIP-1α, MIP-2, and MCP-1) by DCs. Adoptive transfer of BM-DCs exacerbated dextran sulfate sodium colitis while ablation of DCs attenuated the colitis. We conclude that DCs are critical in the development of acute dextran sulfate sodium colitis and may serve a key role in immune balance of the gut mucosa.

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Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells

Abstract: The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-␣

Cited by 62 publications

References 52 publications

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

The Role of Dendritic Cells in the Development of Acute Dextran Sulfate Sodium Colitis

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