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

Abstract

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 IFN-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, and Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

Low-Dose Piperlongumine Rescues Impaired Function of Endothelial Progenitor Cells and Reduces Cerebral Ischemic Injury in High-Fat Diet-Fed Mice

“…The body temperature was maintained at 37 ± 0.5°C throughout the surgical procedure using a heating lamp and pad. Mice were treated with buprenorphine for analgesia on the day of surgery and twice daily thereafter for 72 h ( Duricki et al, 2016 ; Calcagno et al, 2020 ). Behavioral assessment (including Body Asymmetry Test and Beam Test) was performed 3 days after middle cerebral artery occlusion, then mice were euthanized, and their brains were immediately removed.…”

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

“…Single-cell RNA-Seq and high-dimensional immunophenotypic analyses in mouse models and human samples have begun to map neutrophils heterogeneity, highlighting tissue-, differentiation-, and disease-specific adaptations. [190][191][192][193][194] Recent studies in mouse neutrophils from bone marrow, blood, and tissues have characterized the transcriptional dynamics of granulocyte development at steady state and their alterations upon challenge. 190,194 Bacterial infection elicited gene expression changes throughout the spectrum of neutrophil differentiation, boosting effector functions and chemotaxis 194 and reflecting stress-induced mobilization, proliferation, and differentiation of granulocytes.…”

“…192,193,196 ISG-expressing neutrophils with a terminally differentiated phenotype were also detected in the blood of patients with systemic lupus erythematosus 197 or after myocardial infarction. 191 Interestingly, ISG-expressing neutrophils were detected in mouse and human lung cancer 163 198,199 The SiglecF high neutrophil gene signature correlated with poor outcome in patients with lung adenocarcinoma. 199 SiglecF high neutrophils were found to be mobilized in response to signals from bone marrow osteoblasts and to persist for days at the tumor site.…”

“…Single‐cell RNA‐Seq and high‐dimensional immunophenotypic analyses in mouse models and human samples have begun to map neutrophils heterogeneity, highlighting tissue‐, differentiation‐, and disease‐specific adaptations 190‐194 . Recent studies in mouse neutrophils from bone marrow, blood, and tissues have characterized the transcriptional dynamics of granulocyte development at steady state and their alterations upon challenge 190,194 .…”

“…For instance, mass cytometry and scRNA‐Seq analyses of blood leukocytes found increased ISG expression in neutrophils from patients with coronavirus disease COVID‐19 early after infection, 192,193 together with broad alterations of the myeloid compartment in patients with severe disease 192,193,196 . ISG‐expressing neutrophils with a terminally differentiated phenotype were also detected in the blood of patients with systemic lupus erythematosus 197 or after myocardial infarction 191 . Interestingly, ISG‐expressing neutrophils were detected in mouse and human lung cancer 163 but whether these cells contribute to or limit pathology remains an open question.…”