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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 [Bulk_SERIES_1]

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 | GSE156134 | GEO

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

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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 [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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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]

| PRJNA656830 | ENA

GM-CSF signaling strength determines opposing innate memory phenotypes at different stages of myelopoiesis

Project description:Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing self-damage. Here we show that GM-CSF programs myeloid committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream non-committed LKS+ progenitors to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates STAT5, ERK and Akt-mTOR signaling pathways which are essential to establish a training program, whereas in LKS+ progenitors GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared to LKS+ cells. We demonstrate that β-catenin regulation of NF-κB nuclear translocation is central in this process. Glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and PI3K-Akt signaling increases cytoplasmic β-catenin levels to block NF-κB nuclear translocation in myeloid progenitors. In contrast, when ERK and PI3K-Akt signaling is weak, active GSK3 decreases β-catenin to allow NF-κB nuclear translocation in LKS+ progenitors. Finally, GM-CSF-induced LKS+ tolerization can be reversed and takes place in several murine models of trained immunity and in human CD34+ CD38– progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against prolonged cytokine storm.

2023-08-01 | GSE239650 | GEO

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