The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes

Anzai, Atsushi; Choi, Jua; He, Shasha; Fenn, Ashley M.; Nairz, Manfred; Rattik, Sara; McAlpine, Cameron S.; Mindur, John E.; Chan, Christopher T.; Iwamoto, Yoshiko; Tricot, Benoit; Wojtkiewicz, Gregory R.; Weissleder, Ralph; Libby, Peter; Nahrendorf, Matthias; Stone, James R.; Becher, Burkhard; Świrski, Filip K.

doi:10.1084/jem.20170689

Cited by 158 publications

(131 citation statements)

References 49 publications

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“…Inflamed tissues attract DC precursors by releasing a diverse array of molecules, including GM-CSF, chemokines, and ATP (21,35,36). Our study illustrates that adoptive cell therapy with CTLs increases the frequency of tumor DCs in both WT and Zbtb46 bone marrow chimeras, presumably by augmenting proinflammatory signals in the TME (25).…”

Section: Discussionmentioning

confidence: 69%

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Diao

Tang

et al. 2018

The Journal of Immunology

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The success of adoptive CTL therapy for cancer depends on interactions between tumor-infiltrating CTLs and cancer cells as well as other cells and molecules in the tumor microenvironment. Tumor dendritic cells (DCs) comprise several subsets: CD103+CD11b− DC1 and CD11b+CD64− DC2, which originate from circulating precursors of conventional DCs, and CD11b+CD64+ DC3, which arise from monocytes. It remains controversial which of these subset(s) promotes intratumor CTL proliferation, expansion, and function. To address this issue, we used the Zbtb46-DTR–transgenic mouse model to selectively deplete DC1 and DC2 from tumors and lymphoid tissues. Wild-type and Zbtb46-DTR bone marrow chimeras were inoculated with B16 melanoma cells that express OVA and were treated with OT-1 CTLs. We found that depletion of DCs derived from precursors of conventional DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in tumor-draining lymph nodes. By contrast, intratumor CTL accumulation, proliferation, and IFN-γ expression were unaffected by their absence. We found that adoptive cell therapy increases the frequency of monocyte-derived tumor DC3, which possess the capacity to cross-present tumor Ags and induce CTL proliferation. Our findings support the specialized roles of different DC subsets in the regulation of antitumor CTL responses.

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Section: Discussionmentioning

confidence: 69%

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Diao

Tang

et al. 2018

The Journal of Immunology

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“…In the MI model, both IL‐17A and GM‐CSF were shown to be pathogenic and promote the development of heart failure. GM‐CSF was also recently reported to act locally and distally after onset of MI to generate and recruit inflammatory cells . We connected the two pathogenic factors, IL‐17A and GM‐CSF, through the Sca‐1 + cardiac fibroblast subset, which responds to IL‐17A to produce GM‐CSF.…”

Section: Discussionmentioning

confidence: 90%

Sca‐1⁺ cardiac fibroblasts promote development of heart failure

et al. 2018

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The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45 CD31 CD29 mEF-SK4 PDGFRα Sca-1 periostin (Sca-1 ) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1 periostin cardiac fibroblasts (Postn Il17ra ) protected mice from post-infarct heart failure and death. Moreover, Postn Il17ra mice had significantly fewer GM-CSF-producing Sca-1 cardiac fibroblasts and inflammatory Ly6C monocytes in the heart. Sca-1 cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1 cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

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“…Interestingly, far from being a passive actor, the infarcted tissue is also able to modulate circulating leucocyte numbers and tissue damage. Cardiac fibroblasts from infarcted areas secrete GM‐CSF (granulocyte‐macrophage colony‐stimulating factor), which activates bone marrow myeloid progenitors, driving the production of new neutrophils and monocytes, which are then recruited to infarcted areas to further aggravate tissue damage . In the context of AMI, interference with the intravascular activity of neutrophils has proven to be of potential therapeutic value.…”

Section: Vascular Inflammation and Diseasementioning

confidence: 99%

“…Cardiac fibroblasts from infarcted areas secrete GM-CSF (granulocyte-macrophage colony-stimulating factor), which activates bone marrow myeloid progenitors, driving the production of new neutrophils and monocytes, which are then recruited to infarcted areas to further aggravate tissue damage. 83 In the context of AMI, interference with the intravascular activity of neutrophils has proven to be of potential therapeutic value. For example, genetic or pharmacological inhibition of b1-AR dampened intravascular neutrophil crawling and dramatically limited inflammation and myocardial damage.…”

Section: Ischaemia-reperfusion Injurymentioning

confidence: 99%

Neutrophils as effectors of vascular inflammation

Gómez-Moreno

Adrover

Hidalgo

2018

Eur J Clin Investigation

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Vascular inflammation underlies most forms of cardiovascular disease, which remains a prevalent cause of death among the global population. Advances in the biology of neutrophils, as well as insights into their dynamics in tissues, have revealed that these cells are prominent drivers of vascular inflammation though derailed activation within blood vessels. The development of powerful imaging techniques, as well as identification of cells and molecules that regulate their activation within vessels, including platelets and catecholamines, has been instrumental to better understand the mechanisms through which neutrophils protect or damage the organism. Other advances in our understanding of how these leucocytes exert detrimental functions on neighbouring cells, including the formation of DNA-based extracellular traps, constitute milestones in defining neutrophil-driven inflammation. Here, we review emerging mechanisms that regulate intravascular activation and effector functions of neutrophils, and discuss specific pathologies in which these processes are relevant. We argue that identification of pathways and mechanisms specifically engaged within the vasculature may provide effective therapies to treat this prevalent group of pathologies.

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The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes

Cited by 158 publications

References 49 publications

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Sca‐1⁺ cardiac fibroblasts promote development of heart failure

Neutrophils as effectors of vascular inflammation

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The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes

Cited by 158 publications

References 49 publications

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

Sca‐1+ cardiac fibroblasts promote development of heart failure

Neutrophils as effectors of vascular inflammation

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Sca‐1⁺ cardiac fibroblasts promote development of heart failure