ArticleThe Journal of clinical investigation2021
Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 55 citations in OpenAlex.
- Haemolytic injury and cardiovascular disease.Nature reviews. Cardiology · 2026Review
- Article
- PRC1 promotes immunosuppressive macrophages in sepsis via β-catenin/STAT3 signaling.Cellular and molecular life sciences : CMLS · 2026Article
- Erythrocytes as immunomodulators in trauma: orchestrating clearance pathways, inflammation, and organ injury.Frontiers in immunology · 2026Review
- Early warning for acute pyelonephritis with sepsis: risk prediction model for patients without renal medullary necrosis lesions.Frontiers in medicine · 2026Article
- Molecular Mechanisms of Transfusion-Associated Immunomodulation and Its Impact in the Critically Ill.International journal of molecular sciences · 2025Review
- Heme drives cardiac endothelial senescence in sepsis via STING activation.Cell death & disease · 2025Article
- The emerging role of ferroptosis in the pathological development and progression of sepsis.Military Medical Research · 2025Review
- The Nrf2 Activator CDDO-Imidazole Suppresses Inflammation-Induced Red Blood Cell Alloimmunization.Antioxidants (Basel, Switzerland) · 2025Article
- The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps.JCI insight · 2025Article
- The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.Cell death & disease · 2025Article
- CDDO-Imidazole regulates RBC alloimmunization to the KEL antigen by activating Nrf2.bioRxiv : the preprint server for biology · 2025Article
- Immunosenescence in Sepsis: Molecular Mechanisms and Potential Therapeutic Targets.Aging and disease · 2025Review
- Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy.Frontiers in immunology · 2025Review
- Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.PLoS neglected tropical diseases · 2024Article
- Pyrogallol protects against influenza A virus-triggered lethal lung injury by activating the Nrf2-PPAR-γ-HO-1 signaling axis.MedComm · 2024Article
- Increased Neutrophil HResearch square · 2024Article
- Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.Frontiers in immunology · 2024Article
- STAT1 Employs Myeloid Cell-Extrinsic Mechanisms to Regulate the Neutrophil Response and Provide Protection against Invasive Klebsiella pneumoniae Lung Infection.ImmunoHorizons · 2024Article
- Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function.Advances in experimental medicine and biology · 2024Review
Corrections and comments
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Authors and funding
25 authors at 7 institutions in 1 country.
Funding
Abstract
Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent RBCs (sRBCs). Macrophages are also essential in defense against microbial threats, but pathological states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype after intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, in that K. pneumoniae mutants lacking siderophore function recapitulated the findings observed with the WT strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and IFN-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulated the STAT1 pathway, with implications in severe infection.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.