Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination of<i>Histoplasma capsulatum</i>

Gildea, Lucy A.; Gibbons, Reta; Finkelman, Fred D.; Deepe, George S.

doi:10.1128/iai.71.7.3787-3793.2003

Cited by 26 publications

(15 citation statements)

References 40 publications

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“…While IL-4 is known to inhibit the immune response to H. capsulatum , elevation of this cytokine subsequent to the rise in fungal burden suggested that it was a consequence rather than a driver of the altered immune response in Lyz2cre Hif1α fl/fl mice (43, 44). To determine the contribution of IL-4 to the phenotype of Lyz2cre Hif1α fl/fl mice we administered mAb to this cytokine both prior to and during the course of infection.…”

Section: Resultsmentioning

confidence: 99%

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Fecher

Horwath

Friedrich

et al. 2016

The Journal of Immunology

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Hypoxia inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum since granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. Here we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to seven days post-infection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum. The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕ) constituted the majority of IL-10 producing cells. Deletion of HIF-1α in neutrophils or DCs did not alter fungal burden thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕ following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum. IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕ by IFN-γ and effective handling of H. capsulatum.

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Section: Resultsmentioning

confidence: 99%

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Fecher

Horwath

Friedrich

et al. 2016

The Journal of Immunology

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“…Our results showed that methamphetamine induces T cells to produce large amounts of IL-4 and IL-10, and the secretion of these cytokines contributes to the inhibition of T cell proliferation [36,37] after exposure to M antigen and rHSP60 from H. capsulatum. The methamphetamine-induced production of IL-4 and IL-10 likely contributes to enhanced H. capsulatum survival in the host by inhibiting T cell activation and proliferation.…”

Section: Discussionmentioning

confidence: 98%

Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Martinez¹,

Mihu²,

Gácser³

et al. 2009

J INFECT DIS

102

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The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-1 receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.

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“…In secondary infection, the only perturbation was an elevation of IL-4 in recipients of mAb to TNF-␣. It is unlikely that the increased levels of IL-4 impaired clearance of Hc although it is known to directly alter host clearance of this fungus in wild-type mice and to suppress killing of intracellular pathogens (31,35). Previously, we reported that neutralization of TNF-␣ in immunized C57BL/6 mice rechallenged with Hc failed to limit replication of the fungus and succumbed to overwhelming histoplasmosis.…”

Section: Discussionmentioning

confidence: 99%

Protective and Memory Immunity toHistoplasma capsulatumin the Absence of IL-10

Deepe

Gibbons

2003

The Journal of Immunology

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We determined whether the absence of IL-10 in mice influenced protective and memory immunity to Histoplasma capsulatum. IL-10−/− mice cleared primary and secondary infection more rapidly than wild-type controls. Administration of mAb to TNF-α or IFN-γ, but not GM-CSF, abrogated protection in naive IL-10−/− mice; mAb toTNF-α, but not IFN-γ or GM-CSF, subverted protective immunity in secondary histoplasmosis. The inflammatory cell composition in IL-10−/− mice was altered in those given mAb to IFN-γ or TNF-α. More Gr-1+ and Mac-3+ cells were present in lungs of IL-10−/− mice given mAb to IFN-γ, and treatment with mAb to TNF-α sharply reduced the number of CD8+ cells in lungs of IL-10−/− mice. We ascertained whether the lack of IL-10 modulated memory T cell generation or the protective function of cells. The percentage of CD3+, CD44high, CD62low, and IFN-γ+ cells in IL-10−/− mice was higher than that of wild-type at day 7 but not day 21 or 49 after immunization. Fewer splenocytes from immunized IL-10−/− mice were required to mediate protection upon adoptive transfer into infected TCR αβ−/− mice. Hence, deficiency of IL-10 confers a salutary effect on the course of histoplasmosis, and the beneficial effects of IL-10 deficiency require endogenous TNF-α and/or IFN-γ. Memory cell generation was transiently increased in IL-10−/− mice, but the protective function conferred by cells from these mice following immunization is strikingly more vigorous than that of wild-type.

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Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination ofHistoplasma capsulatum

Cited by 26 publications

References 40 publications

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Protective and Memory Immunity toHistoplasma capsulatumin the Absence of IL-10

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