The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages

Autor: Lori B. Daniels, David M Calcagno, Zhenxing Fu, Aaron D. Aguirre, Claire Zhang, Avinash Toomu, Richard P. Ng, Ralph Weissleder, Kenneth Huang, Kevin R. King
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
CCR2
Myeloid
Neutrophils
Myocardial Infarction
Receptor
Interferon alpha-beta
030204 cardiovascular system & hematology
Inbred C57BL
Cardiovascular
Monocytes
Interferon alpha-beta
Mice
0302 clinical medicine
Interferon
Bone Marrow
2.1 Biological and endogenous factors
Aetiology
Mice
Knockout
virus diseases
General Medicine
DNA-Binding Proteins
Heart Disease
medicine.anatomical_structure
Interferon Type I
Female
Receptor
medicine.drug
NF-E2-Related Factor 2
Knockout
1.1 Normal biological development and functioning
Immunology
Biology
Article
Dioxygenases
03 medical and health sciences
Underpinning research
Genetics
medicine
Animals
Humans
Progenitor cell
Heart Disease - Coronary Heart Disease
Innate immune system
Prevention
Inflammatory and immune system
Macrophages
Monocyte
Stem Cell Research
Mice
Inbred C57BL
Good Health and Well Being
030104 developmental biology
Interferon Regulatory Factor-3
Bone marrow
IRF3
Zdroj: Sci Immunol
Science immunology, vol 5, iss 51
Popis: Sterile tissue injury is thought to locally activate innate immune responses via damage associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of interferon-stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors; intensified with maturation at steady-state and after MI; and was controlled by Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2 activation in Ccr2(−) steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcriptional regulators (Tet2, Irf3, Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.
Databáze: OpenAIRE
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