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Hypoxia-inducible factor 1? is Essential for Macrophage-mediated Erythroblast Proliferation in Acute Friend Retrovirus Infection.

ABSTRACT: Macrophages are the frontline of defence against foreign microorganisms, including bacteria, parasites, and viruses. During acute viral infection, macrophages must invade the inflamed tissue toward low oxygen concentrations, where genetic cellular responses depend on hypoxia-inducible factors (HIF). In the study reported here we investigated the role of HIF-1? in macrophage function during acute retroviral infection. Wild-type and myeloid cell-specific HIF-1? knockout mice were infected with Friend retrovirus (FV), and immune response was analysed 7 and 10 days after infection. FV infection led to increased spleen weight in wild-type and knockout mice, whereas a profound proliferation of erythroblasts was seen only in wild-type mice. The number of spleen-infiltrating macrophages was also significantly lower in knockout animals. Macrophage invasion after FV infection in wild-type mice led to elevated amounts of activated macrophage-stimulating 1 protein that resulted in massive proliferation of erythrocyte precursor cells. This proliferation was absent from knockout mice because of impaired invasion capabilities of HIF-1?-deficient macrophages. Our study elucidated a novel mechanism of FV-induced erythrocyte precursor cell proliferation.

SUBMITTER: Schreiber T

PROVIDER: S-EPMC5722883 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Hypoxia-inducible factor 1α is Essential for Macrophage-mediated Erythroblast Proliferation in Acute Friend Retrovirus Infection.

Schreiber Timm T Quinting Theresa T Dittmer Ulf U Fandrey Joachim J Sutter Kathrin K

Scientific reports 20171208 1

Macrophages are the frontline of defence against foreign microorganisms, including bacteria, parasites, and viruses. During acute viral infection, macrophages must invade the inflamed tissue toward low oxygen concentrations, where genetic cellular responses depend on hypoxia-inducible factors (HIF). In the study reported here we investigated the role of HIF-1α in macrophage function during acute retroviral infection. Wild-type and myeloid cell-specific HIF-1α knockout mice were infected with Fri ...[more]

PMID: 29222473

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Project description:Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+ cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+ T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+ T cell responses and accelerated virus control during the first 2 weeks of infection. In vitro experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.IMPORTANCE When infectious agents invade a host, numerous immunological mechanisms are deployed to limit their replication, neutralize their spread, and destroy the host cells harboring the infection. Since immune responses also have a strong capacity to damage host cells and tissues, their magnitude, potency, and duration are under regulatory control. Regulatory T cells are an important component of this control, and the mechanisms that induce them to respond and exert immunosuppressive regulation are of great interest. In the current report, we show that B cells, the cells responsible for making pathogen-specific antibodies, are also involved in promoting the expansion of regulatory T cells during a retroviral infection. In vitro studies demonstrated that they do so via stimulation of the Tregs through interactions between cell surface molecules: GITR interactions with its ligand (GITRL) on B cells and GITR on regulatory T cells. These findings point the way toward therapeutics to better treat infections and autoimmune diseases.

Dataset Information

Hypoxia-inducible factor 1? is Essential for Macrophage-mediated Erythroblast Proliferation in Acute Friend Retrovirus Infection.

Publications

Hypoxia-inducible factor 1α is Essential for Macrophage-mediated Erythroblast Proliferation in Acute Friend Retrovirus Infection.

Similar Datasets

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