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IL1R1-mediated trained myelopoiesis in recurring bacterial infection

ABSTRACT: IL1R1-mediated trained myelopoiesis in recurring bacterial infection

PROVIDER: PRJNA607304 | ENA |

REPOSITORIES: ENA

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [EG_SERIES_3]

Project description:A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of BCG or b-glucan reprograms HSCs in the BM via a type II interferon (IFN-II) or IL1 response, respectively, that confers protective trained immunity against Mtb. Yet, whether BCG/β-Glucan is unique in its ability to induce this protection remains unknown. Herein, we demonstrate that unlike BCG or b-glucan, Mtb reprograms HSCs via IFN-I response that suppresses myelopoiesis and impairs protective trained immunity to Mtb. Mechanistically, IFN-I response dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death in myeloid progenitors. Finally, activation of IFN-I/iron axis in myeloid progenitors generates a detrimental trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the bone marrow that controls the magnitude and anti-microbial capacity of innate immunity to infection

2020-08-13 | GSE156136 | GEO

M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [AERO_SERIES_2]

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

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Transcription profiling of human superficial bladder tumours to delineate the expression pattern differences between non-recurring and recurring tumours

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Trained Immunity Causes Myeloid Cell Hypercoagulability

Project description:Venous thromboembolism is common in individuals with chronic inflammatory diseases, but the pathogenic basis for this increased thrombotic risk remains poorly understood. Myeloid cell ‘trained immunity’ describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a novel maladaptive consequence of trained immunity. LPS stimulation of murine bone marrow-derived macrophages trained previously with either β-glucan or free haem exhibited significantly enhanced procoagulant and antifibrinolytic gene expression and activity compared to macrophages stimulated with LPS alone. The β-glucan training-mediated increase in activated myeloid cell procoagulant activity was mediated by enhanced acid sphingomyelinase-mediated tissue factor (TF) functional decryption. Furthermore, pre-treatment with methyltransferase and acetyltransferase inhibitors to erase epigenetic marks associated with innate immune memory diminished trained macrophage TF gene expression in β-glucan-trained macrophages. Functional analysis of splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Remarkably, monocyte procoagulant activity increased proportionately with time since β-glucan administration, before plateauing at 4 weeks. Furthermore, haematopoietic progenitor cells and bone marrow interstitial fluid isolated from β-glucan-trained mice possessed enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent novel therapeutic vulnerabilities in immunothrombotic disease development, opening new avenues for targeted intervention.

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis

Project description:M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis

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Severe infection constitutively upregulates TIMP1 in the bone marrow hematopoietic niche to support long-term enhanced myelopoiesis

Project description:Infection is able to elicit innate immunological memory by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. The infection experience is imprinted in the bone marrow (BM) stromal cells, in the form of a constitutive upregulation of the tissue inhibitor of metalloproteinases 1 (TIMP1). TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of Notch which in turn suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis post infection. Thus, our data reveal that infection could establish an inflammatory memory in the BM niche to support a long-term enhanced output of innate immune cells.

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

Project description:M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [Bulk_SERIES_1]

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [AERO_SERIES_2]

Project description:M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [AERO_SERIES_2]

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M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [EG_SERIES_3]

Project description:M. tuberculosis reprograms HSCs to limit myelopoiesis and impair trained immunity via a type I IFN/iron axis [EG_SERIES_3]

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