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Researchers identify new factors for inflammation after a heart attack
|Kevin King is the lead author of a paper published in Science Immunology Sept. 25.|
San Diego, Calif., Sept. 30, 2020 -- A team of engineers and physicians at University of California San Diego and Massachusetts General Hospital published new work Sept. 25 in Science Immunology that provides new comprehensive single-cell datasets defining the immune response to a heart attack, from its origins in the bone marrow and its translational potential in the blood, to its diversification and regulation within the heart. They also discovered new immune cell types and regulatory mechanisms.
In the hours and days after a heart attack, immune cells known as neutrophils and monocytes travel from the bone marrow, through the blood, and into the injured heart, where they diversify into specialized cell subsets that orchestrate repair, fibrosis and remodeling.
Defining immune subsets has been challenging due to limitations of fluorescent antibody staining. The researchers, led by Professor Kevin King of the UC San Diego Jacobs School of Engineering and School of Medicine leverage single cell RNA-Seq technology to perform unbiased transcriptome-wide profiling of over 100,000 single cells from the heart, blood, and bone marrow at steady state and at several time points after a heart attack.
Inflammatory signaling after a heart attack was previously thought to result from immune cell interactions with biomolecules from dying cells in the heart. However, the UC San Diego team discovered that subsets of neutrophils and monocytes were pre-activated in the bone marrow before traveling to the distant heart. These interferon-induced cells (IFNICs) express cytokines and chemokines that enhance inflammation and lead to cardiac dysfunction.
The team found similar “priming” of neutrophils and monocytes in human blood, which they believe will enable personalized measurement of patient-specific inflammation after a heart attack.
The team also discovered new regulators of the interferon response. They discovered a population of resident cardiac macrophages that negatively regulates the interferon response to a heart attack by expressing Nrf2-regulated genes. They also found increased bone marrow “priming” of the interferon response in mice lacking Tet2, a gene that when mutated in humans leads to increased cardiovascular events and mortality.
Heart attacks underlie the most common cause of death in the US and the world.
The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages
David M. Calcagno, Claire Zhang, Kevin R. King, UC San Diego Department of Bioengineering, Jacobs School of Engineering
Richard P. Ng Jr, Avinash Toomu, Kenneth Huang, Lor B. Daniels, Zhenxing Fu, Kevin R. King, Division of Cardiology and Cardiovascular Institute, UC San Diego School of Medicine
Aaron D. Aguirre, Ralph Weissleder, Massachusetts General Hospital/Harvard Medical School
Acute ischemic injury to the heart precipitates a strong inflammatory response including influx of myeloid cells expressing type I interferon–stimulated genes (ISGs). Calcagno et al. used single-cell RNA sequencing to probe the origin, evolution, and heterogeneity of this response in the first 4 days after myocardial infarction using human and mouse myeloid cells. Induction of ISG in myeloid cells was initially observed in bone marrow and blood. Post-infarct cardiac tissue in mice contained myeloid subsets with and without ISG expression and a steady-state macrophage population with Nrf2-dependent anti-inflammatory activity. On the basis of their findings, the authors developed an ISG score as a potential biomarker to assess how the vigor of type I interferon signaling influences clinical outcomes after a heart attack.
Jacobs School of Engineering